Sprayable Gel-Type Skin/Mucosa-Adhesive Preparation and Administration System Using the Preparation

ABSTRACT

The present invention provides a sprayable gel-type skin/mucosa-adhesive preparation comprising a gel formulation which contains an active pharmaceutical ingredient in a gel base material comprising a skin/mucosa-adhesive agent and an administration system comprising the preparation.

TECHNICAL FIELD

The present invention relates to a gel-type skin/mucosa-adhesivepreparation comprising an active pharmaceutical ingredient, and anadministration system of the viscous gel-type skin/mucosa-adhesivepreparation comprising an active pharmaceutical ingredient using a spraycontainer for a gel formulation (upper-pressure-relief airless-typespray container) wherein the administration direction of the spraycontainer can be optionally set. Especially, the present inventionrelates to a preparation for nasal drop, and an administration system ofthe preparation using a nasal spray wherein the preparation can beintranasally sprayed, optionally setting the administration direction ofthe spray container, in order to disperse and hold the gel preparationin a broad area of nasal cavity.

BACKGROUND ART

Currently, as a method for administrating a medicament, it is often usedto spray a liquid drug preparation put in a spray container, to a mucosaand skin of a lumen and body surface. Especially, a drug preparation forintranasal administration is often used. The medicaments used for thispurpose had been limited to a regional use such as a treatment forrhinitis. However, these days such administration is getting someattention for the purpose of systemic action. Low-molecular medicamentsfor systemic action such as butorphanol and sumatriptan, and peptidicmedicaments such as calcitonin and desmopressin have been already soldin the market as a drug preparation for intranasal administration, andfurthermore a lot of new applications via intranasal administration havebeen tried to get some absorption-improvement or fast-act.

The merits of a drug preparation for spray-administration to mucosa,especially a drug preparation for intranasal administration include that(1) fast act of a drug is expected because of its rapid absorption, (2)it is possible to avoid the decomposition of a drug due to thefirst-pass in liver, (3) it is possible to avoid the decomposition of adrug due to gastric acid or gastrointestinal enzyme in gastrointestinaltract, (4) it is possible to reduce the dose of a drug because of itshigh bioavailability, (5) it is a noninvasive administration comparedwith injection, (6) a patient can treat himself/herself, (7) a drug candirectly reach the blood circulation or central nervous system, etc.,while the demerits of a drug preparation for intranasal administrationinclude that (1) the dose of a drug which can be administered to nasalcavity is limited to 25-200 μL per one operation, (2) a compound havinga high molecular weight of 1 kD or more is hard to be absorbed via thisroute, (3) the absorption of a drug might be affected by thepathological state of nasal cavity, (4) the state of nasal cavity isvaried between individuals, (5) the elimination system by mucociliaryclearance might affect the absorption of a drug, (6) intranasal enzymebarrier exists, (7) nasal mucosa might be irritated by a drug, etc.Nasal cavity is a site which first gets in contact with the outside, aswell as oral cavity, which have a very outstanding character about theforeign-material-removal and prophylaxis. The abnormal activation ofthese actions or the failure thereby can cause rhinitis, nasal allergy,etc. Especially, pollinosis (hay fever) is becoming a serious socialproblem. For the purpose of the treatment of these nose-localizeddiseases, a lot of nasal spray preparations containing a vasoconstrictoragent, an antiallergic drug, a steroid, etc. have been put on themarket.

Recently, some nasal absorption-type preparations containing a bioactivepeptide or a water-soluble peptide having a molecular weight of1000-3000 have been put on the market. These water-solublehigh-molecular medicaments are ineffectual via oral administration, buteffective only via injection. However, nasal administration can arriveat high bioavailability of several % to several 10 %. The main reasonthereof is thought that the permeability of epithelial layer in nasalmucosa which is an absorption path for water-soluble high-molecularmedicaments is even higher than that of gastrointestinal tract or othermucosa. Thus, a nasal absorption-type preparation containing awater-soluble high-molecular medicament which is expected as asystemically effective formulation, is thought to be very useful as anoninvasive formulation type instead of an injection formulation.

Recently, a nasal absorption-type preparation which can be expected tomitigate an acute pain has been researched/developed as a narcoticanalgesic and a migraine drug, on the basis of the fact that thepermeability of epithelial layer in nasal mucosa is superior to that ofother mucosa. A nasal absorption-type preparation containing such amedicament having central nervous system effect can markedly contributethe improvement of a patient's QOL, because it is expected to exert thepharmacological action more rapidly than a preparation for oraladministration and it is possible to be administered by patient itself.A nasal cavity has a NALT (nasal-associated lymphoid tissue) which issimilar to a lymphoid tissue. These days, some drug preparations forintranasal administration comprising influenza vaccine, diphtheriavaccine, etc. have been researched/developed as a vaccine-administrationroute for airborne-infectible virus, because the nasalimmunoresponsiveness is high. Thus, it is so expected that a drugpreparation for intranasal administration would be developed on thebasis of the anatomical/physiological property of nasal cavity. However,for the drug design thereof it is required to understand theanatomical/physiological property of nasal cavity and surrounding tissuethereof.

A drug preparation for intranasal administration needs creativestrategies because the clearance from nasal cavity is high. Thepreparation types for nasal cavity which have been developed include anointment preparation, a droplet preparation, a spray-type preparation, apowder preparation, etc. These preparations are designed/developed sothat an active medicament should effectively exert its effect in nasalcavity or be absorbed via the nasal cavity, i.e., the intranasaldispersibility of the preparations should be enhanced or the intranasalretention (adhesive property) should be enhanced, in order that thecontacting time between an active medicament and nasal mucosa may belengthened (JP-B-2011069).

An ointment preparation for nasal cavity is not so sanitary because itis usually put on with a finger, and additionally it is difficult toadminister a predetermined amount of an active medicament because it isimpossible to let the medicament reach the mucosa of deep nasal cavitywith a finger.

A droplet preparation has been the most simple preparation for nasalcavity, however, it is difficult to accurately apply a predeterminedamount thereof and further the applied medicament is removed from nasalcavity to pharynx through the mucociliary clearance.

A spray-type preparation is more dispersible than a droplet preparationbecause a liquid preparation can be pumped up, nebulized andintranasally sprayed.

A powder preparation is useful at the time of using a medicamentdecomposable in a solution or when the retention in nasal cavity shouldbe held. However, the intranasal administration of a powder preparationmight sometimes bring about some uncomfortable feelings and disorder ofmucosa, and it is difficult to design a preparation having uniformparticles.

Amongst these drug preparations for intranasal administration, aspray-type preparation is the most common preparation type because ofits simplicity and comfortable feeling. On a spray-type preparation,some trials to enhance the efficacy and the absorption of a medicamenthave carried out by widening the contacting area between a medicamentand nasal mucosa, and -lengthening the contacting time thereof, i.e.,improving the retention of a medicament.

On conventional spray-type preparations, it is recommendable to suck airfrom nose at the time of the spray operation, in order to preventholding a medicament at nasal vestibule or prevent the sprayedpreparation from dripping off from nasal cavity. However, it is thoughtthat the elastic tissue of nasal valve narrows by sucking air, and thenalmost all of the preparation is carried from nose to mouth and finallyswallowed.

The liquid-spraying device which has been usually used in the past ismade for a spray-type preparation for liquid formulation wherein aliquid formulation is pumped up through a tube, which is generally usedat an angle between about 0-25° (see FIG. 3). For this device, it isnecessary to put the tip of the tube in the liquid, and thus the sprayangle of the spray container for administration needs to be set ataround 0° and a patient needs to tilt his/her head forward, which is areason for setting at an angle between about 0-25°. However, using thisadministration system, a normal liquid formulation which has noviscosity or no adhesion, or is low viscosity will instantly run tonostril. On the contrary, using this administration system as a patienttilts his/her head back and the spray angle of the spray container foradministration is set at about 65-90°, a normal spray-type liquidpreparation sprayed will be hit on the intranasal wall such as turbinateand nasal septum, and then drained to inferior meatus of nose because ofits non-adhesion, and mostly ended up being carried to his/her mouth andswallowed. It is partially possible to prevent the liquid from runningto inferior meatus of nose by adding an adhesive polymer mentioned lateras a substrate of the formulation. However, when an adhesive polymer isused therein, it is thought that the particle size of the formulationsprayed gets bigger; the liquid cannot be widely dispersed since thespray spreading-angle from the spray container gets smaller; theparticles collide with each other in a nose to get bigger particleswhich is hit on the wall; and many of the formulation end up beingcarried to a mouth and swallowed. Further, it is expected that theliquid can be spread at a wide area of the turbinate by spraying it withwider spray angle, however, thereby it becomes impossible to put the tipof the tube for pumping up in the liquid in case of a conventionalspray-type preparation. Therefore, there was some limitations toadminister a liquid formulation as a patient tilts his/her head back andthe spray angle of the spray container for administration is set at adesired angle.

In addition, the above-mentioned spray device for liquid is a systemabsorbing external air and thus it is necessary to use a certain amountof an antiseptic agent or other agent.

In addition, the particle size sprayed from the spray device to nasalcavity is also one of the factors to be considered in order to improvethe clearance of a medicament. That is to say, the nasal cavity of ahuman has an area of about 150-180 cm², the distance from nostril tonasopharynx is 12-14 cm as a straight line which is very long, a nasalcavity has an optimized, narrow, and complicated geometric structure inorder to protect the lower respiratory tract, and the narrow slit of thenasal valve causes about a half of the total air-resistance in nasalcavity. Further, there are some spaces partitioned in a slit likepartition with turbinate in the backside of the nasal valve, where thespeed of the formulation particles sprayed slows down and the particlescan be contacted with nasal mucosa and dispersed. However, in suchcomplicated and winding intranasal cavity, the formulation particlessprayed should been easily hit on the intranasal wall to be caught anddeposited. Therefore, most of the formulation particles sprayed to nasalcavity whose particle size is 5 μm or more should be caught by the nasalcavity, then the formulation particles hit on the intranasal turbinatemucosa to be caught and deposited should be carried backward by means ofthe ciliary movement of ciliated cells covering the mucosa, and finally,via posterior nasal cavity and pharynx, drained to the month orswallowed. The countermeasure for the clearance of an active medicamentwhich is taken as a foreign material by cilia and mucus (mucociliaryclearance) is the most important factor on the design of a drugpreparation for intranasal administration. The efficacy and theabsorption of a medicament in nasal mucosa can be decided mainly basedon the retention of a medicament (adhesive property of a formulation)and the permeability of a medicament at the capture part of nasalmucosa. A medicament administered to the effective capture part of nasalmucosa should disappear from the capture part as a simultaneous reactionmainly by means of the removal toward esophagus and respiratory tractdue to the mucociliary clearance and the absorption to nasal mucosa cellvia nasal mucosa. When the removal toward esophagus and respiratorytract from the effective capture part is quick, the clearance for theabsorption to nasal mucosa cell should be reduced and thebioavailability thereof should be reduced. Or, the intranasal area whichthe formulation reaches can be improved to expand when the particle sizeof the sprayed formulation is micrified, however, thereby the risk thatthe formulation could reach lungs increases. Therefore, it has beenunderstood for a skilled person to consider the balance of the particlesize. Accordingly, in order to increase the clearance for the absorptionto nasal mucosa and improve the absorption, it is important to optimizethe particle size of the sprayed formulation, to spray in a suitablespray spreading-angle and an uniform spray spread, and further to addthe retention of a medicament, i.e., adhesive property of a formulationfor nasal mucosa, and thus it has been necessary to add an adhesivepolymer as a base material for formulation to improve the property.

In theory, it is possible to spray a formulation for nose to take theformulation to the backside of the nasal valve by controlling theparticle size of the sprayed formulation in a size of not more than 50μm using a nebulizer, and inbreathing the sprayed particles at the timeof spraying. However, using particles in a size of not more than 50 μm,a half or more of the particles should reach bronchi or lung, and thus amedicament to be held in intra cavity should disappear and additionallyan undesirable side effect might happen. Further, the device for sprayoperation such as a nebulizer is expensive, and there was not anyinexpensive and simple system to spread a formulation having aneffective particle size in a whole intranasal cavity.

In order to improve the retention of a spray-type preparation inintranasal cavity, the present inventors have invented a gel basematerial for spray-administration to mucosa or skin, and have alreadydisclosed a sprayable gel base material and a sprayable gel preparationcomprising said base material and an active medicament, which can beapplied to nasal cavity that is a mucosa site and is possible to use asa high-spreading spray-type preparation for nose (JP-B-2011069).

However, it has been already known as a serious problem that theviscosity should be reduced through spray operation even when a highviscous sprayable gel preparation is sprayed.

In addition, it is sometimes difficult to keep a constant amount of onespray shot when the spray angle for administration is rapidly changed,etc. because the sprayable gel-type preparation adheres on the sidewallof the spray container in being used as a spray-type preparation due toits high viscosity, the residual rate that indicates an unsprayedformulation retained in the container is high compared with aconventional liquid formulation, and the preparation cannot flow easilyand rapidly in the spray container. Furthermore, it is also a problemthat the formulation particles sprayed hardly reach the deep nasalcavity due to their particle size distribution, and it is difficult toadjust the spray spreading-angle and to spray in a uniform spray spread.

On a preparation for spray-administration to skin, there are also somesimilar problems to the above-mentioned preparation using a nasal spraysuch as the retention of the preparation, and the spray angle of thespray container for administration.

DISCLOSURE OF INVENTION Problems to Be Solved by Invention

As mentioned above, with regard to a drug preparation forspray-administration to mucosa such as nasal cavity, eye, ear, oralcavity, rectum, vagina, and urethra, especially spray-type preparationfor nose, it has been improved to some extent in case that sprayable gelbase material is used as a liquid for formulation in order to improvethe retention of the liquid. However, when a conventional spray devicefor nose is used, the above-mentioned problems such as high residualrate and inconstant spray amount may remain due to its retention andthere is also a problem that the viscosity of a liquid for formulationis decreased by spray operation, and therefore it has been necessary toimprove such problems. In addition, it is necessary to use a certainamount of an antiseptic agent or other agent because a conventionalspray device for nose is a system absorbing external air, and thus someimprovements have been necessary for safety and production cost.

Furthermore, from the viewpoint of the complicated structure ofintranasal cavity, it is one of useful methods that the spray angle foradministration is adjusted for the structure of intranasal cavity sothat the sprayed formulation can be spread to a wide area of theturbinate, however, there is a certain limitation of the spray angle foradministration of a liquid formulation using a conventional spray-typepreparation for nose. Therefore, it has been desired to develop a newadministration system capable of spraying at a suitable angle andspreading a sprayed formulation to a wide area of the turbinate and anew formulation for nasal spray capable of such system.

In addition, there have been also similar problems to theabove-mentioned formulation for nasal spray on a drug preparation forspray-administration to skin such as hand, finger, leg, body, groin,scalp, the surround of anus, and the surround of genitalium.

Means to Solve the Problem

The present inventors have extensively studied on the above problem andhave found an administration system comprising the sprayable gel-typeskin/mucosa-adhesive preparation which is put in a spray container for agel formulation (upper-pressure-relief airless-type spray container)that is different from a conventional spray container for nasal drop,which is characterized in that the administration direction of the spraycontainer can be optionally set, i.e., the gel base material can besprayed at any angle. Based upon the new findings, the present inventionhas been accomplished. In detail, it has got possible to prepare theabove desired gel-type skin/mucosa-adhesive preparation by containing acertain constant amount of carboxy vinyl polymer and/or gellan gum inskin/mucosa-adhesive agent. Particularly, the inventors have found thatthe addition of gellan gum can prevent the viscosity of the preparationfrom lowering with nasal discharge, etc.

In addition, the inventors have found that it is possible to adjust theviscosity of the above formulation by adding an outside shearing forceto the formulation to prepare a formulation having comparatively highviscosity (for example, 10000 mPa·s to 50000 mPa·s), which can make itpossible to spray uniformly and completely prevent the viscosity of theformulation from lowering via the spray operation. Furthermore,surprisingly it has found that the viscosity of the formulation can beadjusted by adding a viscosity modulating agent and an outside shearingforce so that the spray spreading-angle of the spray container and thespray spread can be set to meet the desired treatment. That is to say,the present inventors have found that the following tendency. Withregard to a gel-type mucosa-adhesive preparation wherein the viscosityis adjusted with a shearing force, the spray spreading-angle sprayedfrom a spray container tends to be narrowed. On the contrary, in thecase of adding a shearing force together with a viscosity modulatingagent, the spray spreading-angle sprayed tends to be widen. Using thisprinciple, it is possible to adjust the spray spreading-angle controlledto meet the purpose without using a variety of spray containers. Inaddition, the spray spread sprayed from a spray container tends to belocalized at the periphery in using a gel-type mucosa-adhesivepreparation adjusted with only a viscosity modulating agent without anyshearing force. However, thanks to the finding that it is possible tospray in uniformity by adding a shearing force, it is possible tocontrol the spray spread to meet the purpose by using these factors.

Furthermore, although such gel-type skin/mucosa-adhesive preparation ishard to be steadily sprayed because of its viscosity and adhesiveproperty, and additionally it is hard to spray out the preparation inthe container, it has been found that a spray container for a gelformulation (upper-pressure-relief airless-type spray container) canmake it possible to spray in a constant amount and markedly improve theresidual rate at the time of spraying out.

Especially, the present preparation for nasal spray using theformulation and the system can make it possible to spread theformulation to a wide area of the turbinate when spraying it to nasalcavity setting the body position for administration (the angle ofpatient's head) and the spray container at the effective angle.

Practically, the present invention provides a sprayable gel-typeskin/mucosa-adhesive preparation comprising a gel formulation whichcontains an active pharmaceutical ingredient in a gel base materialcomprising a skin/mucosa-adhesive agent.

The present invention provides the above-mentioned sprayable gel-typeskin/mucosa-adhesive preparation, wherein the applied mucosa is a mucosaof nasal cavity, eye, ear, oral cavity, rectum, vagina, or urethra; orthe applied skin is a skin of hand, finger, leg, body, groin, scalp, thesurround of anus, or the surround of genitalium. Especially, the presentinvention provides a gel-type mucosa-adhesive preparation for nasalspray comprising a gel formulation which contains an activepharmaceutical ingredient in a gel base material comprising amucosa-adhesive agent.

In addition, the present invention provides the above-mentionedsprayable gel-type skin/mucosa-adhesive preparation, wherein theskin/mucosa-adhesive agent comprises carboxy vinyl polymer and/or gellangum. Furthermore, the present invention provides the above-mentionedsprayable gel-type skin/mucosa-adhesive preparation, wherein theskin/mucosa-adhesive agent contains 0.1 %(w/w) to 2.0 %(w/w) carboxyvinyl polymer or gellan gum, or contains carboxy vinyl polymer andgellan gum in a total amount of 0.2% (w/w) to 4.0 %(w/w).

In addition, the present invention provides the above-mentionedsprayable gel-type skin/mucosa-adhesive preparation, wherein theskin/mucosa-adhesive agent contains 0.1% (w/w) to 2.0% (w/w) carboxyvinyl polymer, and the viscosity thereof is adjusted by adding anoutside shearing force. The adjusted viscosity is generally 50 mPa·s to5000 mPa·s, preferably 100 mPa·s to 4000 mPa·s, more preferably 500mPa·s to 3000 mPa·s, and the most preferably 2000 mPa·s to 2500 mPa·s.

Additionally, the present invention provides the above-mentionedgel-type skin/mucosa-adhesive preparation for nasal spray, whichcomprises 0.1% (w/w) to 2.0% (w/w) carboxy vinyl polymer as askin/mucosa-adhesive agent,

wherein by adding a viscosity modulating agent and an outside shearingforce, the viscosity thereof is adjusted to make a comparativelyhigh-viscous preparation (e.g. the viscosity of 10000 mPa·s to 50000Mpa·s), and the spray spreading-angle from the spray container and thespray spread can be optionally set to meet the desired treatment. Theinventor has found that the spray spreading-angle tends to become narrowby subjecting the gel formulation to the outside shearing force. Thenarrowed spray spreading-angle can be widened by adding a viscositymodulating agent, and thus the spray spreading-angle can be controlledthrough the two factors to meet the desired treatment. In addition, theoutside shearing force can make the spray spread (which is localized atthe periphery by adjusting only with a viscosity modulating agent)uniformalized. Therefore, from the viewpoint of this merit, the shearingforce is useful to control the desired spray spread.

The viscosity modulating agent in the invention is preferably selectedfrom a group consisting of sodium chloride, potassium chloride andcalcium chloride. The controlled viscosity is generally 50 mPa·s to 5000mPa·s, preferably 100 mPa·s to 4000 mPa·s, more preferably 500 mPa·s to3000 mPa·s, and the most preferably 2000 mPa·s to 2500 mPa·s.

In addition, the present invention provides the above-mentionedsprayable gel-type skin/mucosa-adhesive preparation comprising athickening agent for carboxy vinyl polymer which is selected fromneutral or basic water-soluble amino acids and is contained in theweight range of 1:0.5 to 1:3 (preferably 1:1 to 1:2) against carboxyvinyl polymer. Furthermore, the thickening agent for carboxy vinylpolymer is preferably arginine, lysine, and/or ornithine.

And the present invention provides the above-mentioned sprayablegel-type skin/mucosa-adhesive preparation, wherein the gel formulationcontains an active pharmaceutical ingredient in an amount of 0.001-10%(w/w) in the gel formulation.

Further, the present invention provides the above-mentioned sprayablegel-type skin/mucosa-adhesive preparation, wherein the activepharmaceutical ingredient is in a dissolved, suspended, or emulsifiedstate.

The present invention provides an administration system comprising theabove-mentioned sprayable gel-type skin/mucosa-adhesive preparationwhich is put in a spray container for a gel formulation(upper-pressure-relief airless-type spray container), which ischaracterized in that the administration direction of the spraycontainer can be optionally set in order to spray the preparation to anaffected part for the treatment, i.e., the gel base material can besprayed at any angle. Especially, the present invention provides anadministration system comprising the sprayable gel-type mucosa-adhesivepreparation which is put in a spray container for a gel formulation(upper-pressure-relief airless-type spray container), wherein thepreparation can be intranasally sprayed, optionally setting the sprayspreading-angle from the spray container, in order to disperse and holdthe gel preparation in a broad area of nasal cavity.

The present invention provides the above-mentioned administrationsystem, wherein the viscosity of the gel formulation is in the rangebetween 50 mPa·s and 5000 mPa·s (preferably 100 mPa·s and 4000 mPa·s),and the particle of the formulation sprayed via the spray operation hasa viscosity retention rate of 50% or more.

The present invention provides the above-mentioned administrationsystem, wherein the viscosity of the gel formulation is adjusted in therange between 50 mPa·s and 5000 mPa·s by adding an outside shearingforce, and the particle of the formulation sprayed via the sprayoperation has a viscosity retention rate of 90% or more.

The present invention provides the above-mentioned administrationsystem, wherein the mean particle size of the formulation sprayed is inthe range between 10 μm and 100 μm (preferably between 50 μm and 100μm).

The present invention provides the above-mentioned administrationsystem,

wherein by adding an outside shearing force (optionally adding viscositymodulating agent), the viscosity of the gel formulation is adjusted inthe range between 50 mPa·s and 5000 mPa·s, the spray spreading-anglefrom the spray container is set in the range between 10° and 70°, andthe spray spread is set in from uniformity through the periphery inorder to meet the desired treatment.

The present invention provides the above-mentioned administrationsystem, characterized in that the rate of the gel formulation staying inthe spray container is not more than 20 % (preferably not more than 15%,more preferably not more than 10%) when the spray operation has beencompletely impossible through the use, and the rate of the gelformulation sprayed in the range of the prefixed amount+10% is not lessthan 70% (preferably not less than 80%).

The present invention provides the above-mentioned administrationsystem, wherein the spray angle of the spray container foradministration can be set in any or all angle between 0° and 360°. Inaddition, the present invention provides the above-mentionedadministration system for nasal spray, wherein the spray angle of thespray container for administration can be set in any or all anglebetween 45° and 180°.

The present invention provides the above-mentioned administrationsystem, characterized in that the addition of an antiseptic agent or apreservative is omitted, or the said additive to be added to theformulation is decreased to 50% or less of the usual amount level.

The present invention also provides the above-mentioned administrationsystem wherein a ring for reducing useless space is set in a spraycontainer for a gel formulation (upper-pressure-relief airless-typespray container), the body of slidable valve has a tilt angle of 5-30°(preferably 15-25°), and the ring also has the same tilt angle.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows a spray container for a gel formulation(upper-pressure-relief airless-type spray container) used herein. Theright half plane of the drawing shows a cross-sectional view to see aninternal structure.

FIG. 2 shows a magnified figure of the main part in the cross-sectionalview shown in FIG. 1 of the spray container for a gel formulation(upper-pressure-relief airless-type spray container). The right halfplane shows a container wherein the body of slidable valve has a certaintilt angle (as an example, 20° in the drawing) which is a feature of thepresent invention, while the left half plane shows a conventionalupper-pressure-relief airless-type spray container.

FIG. 3 shows some states that the present preparation for nasal spray isinserted in human turbinate (nasal meatus) in various angles andadministered. It is defined as an angle of 0° that the spray preparationis set vertically. The figures show 7 examples administered in 25°, 45°,65°, 90°, 135° and 180°.

FIG. 4 shows the stability regarding the amount sprayed from each spraycontainer, under the condition of the viscosity: 1000 mPa·s (spray anglefor administration: 0°).

FIG. 5 shows the stability regarding the amount sprayed from each spraycontainer, under the condition of the viscosity: 2000 mPa·s (spray anglefor administration: 0°).

FIG. 6 shows the stability regarding the amount sprayed from each spraycontainer, under the condition of the viscosity: 3600 mPa·s (spray anglefor administration: 0°).

FIG. 7 shows the stability regarding the amount sprayed from each spraycontainer, under the condition of the spray angle for administration:450 (viscosity: 2000 mPa·s).

FIG. 8 shows the stability regarding the amount sprayed from each spraycontainer, under the condition of the spray angle for administration:650 (viscosity: 2000 mPa·s).

FIG. 9 shows the stability regarding the amount sprayed from each spraycontainer, under the condition of the spray angle for administration:90° (viscosity: 2000 mPa·s).

FIG. 10 shows the figure of the spray spread that is observed in Example5 wherein the viscosity is adjusted to 2500 mPa·s by -adding 0 % sodiumchloride and an outside shearing force.

FIG. 11 shows the figure of the spray spread that is observed in Example6 wherein the viscosity is adjusted to 2500 mPa·s by adding 0.125%sodium chloride and an outside shearing force.

FIG. 12 shows the figure of the spray spread that is observed in Example7 wherein the viscosity is adjusted to 2500 mPa·s by adding 0.25% sodiumchloride and an outside shearing force.

FIG. 13 shows the figure of the spray spread that is observed in Example8 wherein the viscosity is adjusted to 2500 mPa·s by adding 0.50 %sodium chloride, without outside shearing force.

FIG. 14 shows the variation in the viscosity of Example 4-Example 10 andthe comparative example by adding a prepared nasal discharge.

BEST MODE FOR CARRYING OUT THE INVENTION

The gel base material herein denotes a base material comprising awater-soluble polymer compound as a mucosa-adhesive agent, and waterand/or alcohol(s), which has viscous property. The gel base material mayinclude an antiseptic agent, a preservative, an isotonic agent, a pHregulator, a coloring agent, etc. which are conventionally used inpharmaceuticals.

The water-soluble polymer compound which is used as askin/mucosa-adhesive agent (adhesive polymer) in the present invention,includes gum arabic, sodium alginate, propylene glycol alginate, carboxyvinyl polymer, carmellose sodium, xantham gum, gellan gum, gelatin,hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, methylcellulose, etc. It is possible touse a mucosa-adhesive agent prepared by combining 2 or more of theabove-mentioned ingredients. Further, in order to (1) make the presentformulation possess skin/mucosa-adhesiveness, (2) make the viscositythereof retained or little changed through the spraying operation, (3)make the present formulation get to a target site (intranasal in thecase of nasal use) with keeping the high viscosity, and (4) make thepresent formulation sprayed in a mean particle size of 10-100 μm(preferably 50-100 μm) which is enough fine, simultaneously; a gel basematerial comprising carboxy vinyl polymer or gellan gum, or acombination of carboxy vinyl polymer and gellan gum is preferably usedas the adhesive polymer. As the base material comprising carboxy vinylpolymer, the gel base described in JP-B-2011069 “Spray gel base andspray gel preparation using thereof” whose inventor is the same as thepresent inventor may be used.

In addition, the gel base material may be controlled by (1) adjustingthe viscosity of the formulation by adding an outside shearing force tocarboxy vinyl polymer, or (2) adjusting the viscosity of the formulationby adding a viscosity modulating agent and an outside shearing force tocarboxy vinyl polymer, so that the spray spreading-angle of the spraycontainer and the spray spread can be set to meet the desired treatment.

The operation giving the shearing force herein can be carried out via amethod known by a skilled person, wherein for example, a high-speedspinning-type emulsifying device, a colloidal mill-type emulsifyingdevice, a high-pressure emulsifying device, a roll mill-type emulsifyingdevice, an ultrasonic-type emulsifying device and a membrane-typeemulsifying device can be used as a device giving shearing force.Especially, a homo mixer-type, a comb-type, and anintermittently-jet-stream-generating-type, high-speed spinning-typeemulsifying devices are preferable.

The viscosity to be adjusted herein is ordinarily 50 mPa·s to 5000mPa·s, preferably 100 mPa·s to 4000 mPa·s, more preferably 500 mPa·s to3000 mPa·s, and most preferably 2000 mPa·s to 2500 mPa·s.

And, the spray spreading-angle used herein is defined as 0° when the gelformulation is sprayed in a straight line from the spray nozzle; andmeans an angle spreading from angle 0° that the gel formulation issprayed. And, the spray spread means an index which indicates uniformityon the spread of the gel formulation sprayed. For example, it is denotedas “sprayed in uniformity”, “localized at the periphery”, etc. Thisevaluation of the spray spread was carried out by visually observing thegel formulation which was sprayed for a board from the spray nozzle andthen adhered on the board.

The carboxy vinyl polymer which is used as an adhesive polymer in thepresent invention means a water-soluble polymer obtained by thepolymerization with an acrylic acid used as a main ingredient, andincludes a conventional polymer, for example, Carbopol® (Noveon, USA),etc. The concentration of carboxy vinyl polymer used in the presentinvention is generally about 0.1-2.0% (w/w). Gellan gum which is apolysaccharide produced by a microorganism, Sphingomonas elodea, isgenerally used in a variety of food, etc. Especially, low acetyl gellangum whose trade name is Gelrite®, and so on are preferably used. Theconcentration of gellan gum used in the present invention is generallyabout 0.1-2.0% (w/w). When carboxy vinyl polymer and gellan gum are usedsimultaneously and the formulation containing the two ingredients issprayed and contacted with a nasal discharge (nasal mucus), thesensitivity of the nasal discharge (nasal mucus) against the ion of theformulation is reverse, thus the viscosity thereof gets lowered at firstand the formulation once spreads in a wide area of a nasal cavity, andthen the viscosity is retained (increased) to make it possible to longstay in a nasal cavity, which is an ideal profile. The totalconcentration of carboxy vinyl polymer and gellan gum used in thepresent invention is generally 0.2-4.0 % (w/w), and the ratio of both isadjusted responding to the viscosity shift at a time when theformulation including an active medicament is contacted with nasaldischarge (nasal mucus).

The thickening agent which is used for thickening carboxy vinyl polymermeans a water-soluble basic material, which can neutralize and thenionize an acidic carboxy vinyl polymer, and thereby structurally magnifythe carboxy vinyl polymer to thicken the carboxy vinyl polymer; andincludes, for example, an inorganic base such as sodium hydroxide andpotassium hydroxide; and an organic base such as an amine (e.g.diisopropanolamine, triethanolamine, and tripropanolamine), an aminoacid (e.g. arginine, lysine, and ornithine); and preferably arginine,lysine, and ornithine. The thickening agent belonging to the amino acidabove is generally contained in the weight range of 1:0.5 to 1:3,preferably 1:1 to 1:2 against carboxy vinyl polymer. The pH of thewater-soluble basic material mentioned above may be adjusted to thedesired range by neutralizing the carboxy vinyl polymer. The thickeningagent may be used in combination with two or more of the abovematerials.

The “active pharmaceutical ingredient” dissolved in the gel basematerial herein means a pharmaceutical agent which is generallyadministered to the area of skin and/or mucosa, for example, apharmaceutical agent for topically treating inflammation, allergy, etc.,and a pharmaceutical agent which is expected to act on whole bodythrough absorption from mucosa such as percutaneous absorption and nasalabsorption are exemplified, but are not limited to them. The activepharmaceutical ingredient of the present invention which can beadministered to the area of skin and/or mucosa includes, for example, alocal vasoconstrictor such as naphazoline nitrate, tetrahydrozolinehydrochloride, oxymetazoline hydrochloride, and tramazolinehydrochloride; a steroid such as hydrocortisone, prednisolone,triamcinolone acetonide, dexamethasone phosphate, flunisolide,betamethasone phosphate, sodium beclomethasone dipropionate ,fluticasone propionate, mometasone furoate, fluticasone furoate,budesonide, ciclesonide, betamethasone butyrate propionate, anddiflucortolone valerate; a nonsteroidal antiinflammatory drug such asaspirin, mefenamic acid, ibuprofen piconol, suprofen, bufexamac,bendazac, ufenamate, diclofenac sodium, indomethacin, felbinac,ketoprofen, flurbiprofen, naproxen, pranoprofen, loxoprofen sodium,alminoprofen, zaltoprofen, piroxicam, meloxicam, lornoxicam, celecoxib,and rofecoxib; an antihistamine such as diphenhydramine, clemastinefumarate, triprolidine hydrochloride, isothipendyl hydrochloride,alimemazine tartrate, chlorpheniramine maleate, and promethazinehydrochloride; an anti-allergic agent such as cromolyn sodium,tranilast, ketotifen fumarate, amlexanox, azelastine hydrochloride,oxatomide, levocabastine hydrochloride, fexofenadine hydrochloride,epinastine hydrochloride, ebastine, cetirizine hydrochloride,bepotastine besilate, olopatadine hydrochloride, loratadine, ozagrelhydrochloride, seratrodast, pranlukast hydrate, zafirlukast, montelukastsodium, and suplatast tosilate; an antimicrobial agent such asnadifloxacin, clindamycin phosphate, levofloxacin, cefcapene pivoxilhydrochloride hydrate, clarithromycin, cefditoren pivoxil, vancomycinhydrochloride, meropenem hydrate, flomoxef sodium, cefotiam hexetilhydrochloride, and orbifloxacin; an antiherpesvirus drug such asacyclovir, valacyclovir hydrochloride, and vidarabine; ananti-cytomegalovirus agent such as ganciclovir, and foscarnet sodiumhydrate; an anti-influenza virus agent such as oseltamivir phosphate,and zanamivir hydrate; an antifungal agent such as amphotericin B,fluconazole, itraconazole, micafungin sodium, terbinafine hydrochloride,neticonazole hydrochloride, lanoconazole, luliconazole, liranaftate,butenafine hydrochloride, and amorolfine hydrochloride; an antisepticagent such as povidone-iodine, benzalkonium chloride, benzethoniumchloride, and chlorhexidine gluconate; a local anesthetic such aslidocaine and dibucaine; an immunosuppressive agent such as cyclosporineand tacrolimus hydrate; an active vitamin D₃ drug such as tacalcitol,calcipotriol, alfacalcidol, calcitriol, and maxacalcitol; a drug fortreating alopecia such as minoxidil and carpronium chloride; a drug fortreating skin ulcer such as aluminum chlorohydroxy allantoinate,tretinoin tocoferil, bucladesine sodium, alprostadil alfadex, andtrafermin; a vitamin B₁₂ drug such as cyanocobalamin and mecobalamin; avitamin K drug such as phytonadione and menatetrenone; an antiplasminsuch as epsilon-aminocaproic acid and tranexamic acid; an antiepilepticdrug such as clonazepam, carbamazepine, and zonisamide; a hypnotic suchas triazolam, brotizolam, zolpidem tartrate, quazepam, nitrazepam, anddiazepam; an antidepressant such as paroxetine hydrochloride hydrate,etizolam, fluvoxamine maleate, milnacipran hydrochloride, and imipraminehydrochloride; an antipsychotic agent such as olanzapine, risperidone,and quetiapine fumarate; a drug for treating dementia such as donepezilhydrochloride and nicergoline; a drug for treating Parkinson's diseasesuch as apomorphine, cabergoline, pergolide mesilate, bromocriptinemesilate, amantadine hydrochloride, and droxidopa; a drufg for treatingcerebroprotective such as edaravone; an analgesic such as morphine,oxycodone, fentanyl, buprenorphine hydrochloride, and butorphanoltartrate; a stop smoking aid such as nicotine; a drug for treatingmigraine such as ergotamine tartrate, sumatriptan, zolmitriptan,eletriptan hydrobromide, rizatriptan benzoate, naratriptan,frovatriptan, almotriptan, and avitriptan; a vitamin such ascyanocobalamin, and mecobalamin; a sex steroid hormone such asestradiol, estriol, progesterone, and testosterone; a metaldetoxification agent such as deferoxamine mesylate; anantitussive/antitussive drug such as codeine phosphate and isoproterenolhydrochloride; an antiemetic such as ondansetron hydrochloride,ramosetron hydrochloride, tropisetron hydrochloride, granisetronhydrochloride, metoclopramide, domperidone, and mosapride citrate; ananticancer agent such as goserelin acetate, bicalutamide, tegafur,paclitaxel, tamoxifen citrate, gemcitabine hydrochloride, doxifluridine,capecitabine, imatinib mesilate, rituximab, gefitinib, trastuzumab,paclitaxel, and docetaxel hydrate; an antihypertensive agent such ascandesartan cilexetil, valsartan, losartan potassium, telmisartan,olmesartan medoxomil, amlodipine besylate, nifedipine, benidipinehydrochloride, nicardipine hydrochloride, nilvadipine, azelnidipine,manidipine hydrochloride, diltiazem hydrochloride, enalapril maleate,imidapril hydrochloride, temocapril hydrochloride, perindopril erbumine,carvedilol, bisoprolol fumarate, propranolol hydrochloride, andatenolol; a drug for treating dysuria such as tamsulosin hydrochlorideand naftopidil; an antiulcer drug such as cimetidine, ranitidinehydrochloride, famotidine, and nizatidine; a cardiotonic agent such asdopamine hydrochloride and dobutamine hydrochloride; a bronchodilatorsuch as fenoterol hydrobromide, ipratropium bromide, and oxitropiumbromide; an anti-obesity agent such as mazindol and peptide YY; anautonomic agent such as neostigmine methylsulfate; a drug for treatingangina such as nitroglycerin, isosorbide dinitrate, and nicorandil; anantiplatelet agent such as ticlopidine hydrochloride, cilostazol,sarpogrelate hydrochloride, and beraprost sodium; an antidiabetic drugsuch as voglibose, acarbose, glimepiride, nateglinide, metforminhydrochloride, pioglitazone hydrochloride, and gliclazide; alipid-lowering drug such as pravastatin sodium, simvastatin, fluvastatinsodium, atorvastatin calcium hydrate, pitavastatin calcium, rosuvastatincalcium, and bezafibrate; an antiarrhythmic drug such as pilsicainidehydrochloride, mexiletine hydrochloride, and disopyramide phosphate; amuscle relaxant such as baclofen, piracetam, eperisone hydrochloride,and tizanidine hydrochloride; an antirheumatic drug such as bucillamine,methotrexate, infliximab, prednisolone farnesylate, and actarit,additionally an LHRH (luteinizing hormone-releasing hormone) as apeptide/proteinaceous drug; a growth hormone-releasing factor; asomatostatin derivaative; a posterior pituitary hormone such asvasopressin and desmopressin acetate; an oxytocin; a hirudin derivative;an enkephalin; a ACTH (adrenocorticotropic hormone) derivative; abradykinin derivative; an insulin; a glucagon derivative; a growthhormone; a growth hormone-releasing hormone; a luteinizing hormone; aninsulin-like growth factor; a calcitonin gene-related peptide; an atrialnatriuretic peptide derivative; an interferon; an interleukin; anerythropoietin; a granulocyte colony-stimulating factor; a macrophagecolony-stimulating factor; a parathyroid hormone; parathyroidhormone-releasing hormone; a prolactin; a thyrotropin-releasing hormone;an angiotensin; a calcitonin; a Gn-RH (Gonadotropin releasing hormone)derivative such as leuprorelin acetate, buserelin acetate, and nafarelinacetate; a thrombolytic drug such as tisokinase, alteplase, monteplase,pamiteplase, and nasaruplase; a vaccine such as influenza HA vaccine,pneumococcal vaccine, and recombinant adsorbed hepatitis B vaccine. Theactive pharmaceutical ingredient may be contained in 0.001-10% (w/w),but the content thereof is not limited. And the gel formulation maycontain plural active pharmaceutical ingredients.

When an active medicament insoluble in water is used, a formulationcontaining the medicament may become clouded. However, the activemedicament is not precipitated and hence it is no problem to use it viaa normal spray operation. On the contrary, it is preferable to use asolubilizer in the formulation or to prepare the formulation with theactive medicament that is dissolved in a water-soluble organic solventin advance, when an active medicament soluble in a formulation can bemore absorbed in a target site (nasal mucosa in case of nasal spray).The water-soluble organic solvent includes a lower alcohol such asethanol and isopropanol; a glycol such as propylene glycol, 1,3-butyleneglycol, and polyethylene glycol having a molecular weight of 300-500. Inaddition, the solubilizer used herein can be selected from a variety ofsurfactants, depending on the solubility of the active medicament.

In addition, it is useful to suspend an active medicament by adding anappropriate suspending-agent. The suspending agent includes, forexample, a variety of surfactants such as a sucrose fatty acid ester,polyoxyl 40 stearate, polyoxyethylene (60) hydrogenated castor oilpolyoxyethylene, polysorbate 80, glyceryl monostearate, sorbitanmonostearate, and sorbitan monopalmitate.

Further, it is also useful to emulsify the gel base material by addingan appropriate emulsifying agent and then to add an active medicamentthereto; or to emulsify the active medicament itself. The emulsifyingagent used herein can be selected from a variety of surfactants.

The term “mucosa” used herein refers to an epithelial layer originatedfrom ectoderm, covered in epithelial cell; and as an example thereof,nasal cavity, eye, ear, oral cavity, rectum, vagina, genitalium,urethra, anus, etc. are exemplified. And, the term “skin” used hereinrefers to a layer covering body surface; and the example thereofincludes a layer of hand, finger, leg, body, groin, scalp, the surroundof anus, the surround of genitalium, etc.

The term “skin/mucosa” used herein means “skin and/or mucosa,” which isused in order to cover a target site that has both skin and mucosa, suchas the surround of anus, or the surround of genitalium.

The viscosity defined herein can be measured, for example, by theviscosity measurement by capillary tube viscometer, the viscositymeasurement by rotational viscometer, etc., which are described inViscosity Determination in the Japanese Pharmacopoeia (General Testssection).

The viscosity of the gel formulation used herein is generally 50 mPa·sto 5000 mPa·s, preferably 100 mPa·s to 4000 mPa·s, more preferably 500mPa·s to 3000 mPa·s, and most preferably 2000 mPa·s to 2500 mPa·s.

The term “viscosity retention rate” defined herein refers to a rate ofthe viscosity of the formulation particle that has just been sprayedagainst that of the pre-sprayed gel formulation.

In the present invention, the viscosity retention rate of theformulation particle sprayed via the present spray operation ispreferably 50% or more.

The mean particle size of the formulation particle sprayed in thepresent invention can be measured for example with a particle sizeanalyzer which uses a laser light scattering method.

The mean particle size thereof in the present invention is preferably inthe range of 10 μm to 100 μm, and further preferably in the range of 50μm to 100 μm.

The “residual rate” defined herein refers to a rate of the amount of thegel formulation which stays in the spray container for a gel formulation(upper-pressure-relief airless-type spray container) at the time whenthe gel-type mucosa-adhesive preparation for nasal drop is sprayed outand the spray operation cannot be carried out, per the total amountbefore using.

The residual rate of the present invention is generally 20% or less,preferably 15% or less, and more preferably 10% or less.

The “prefixed amount” defined herein refers to an amount or amount-rangeof the formulation that is sprayed through one-shot of the nasal spray,which is fixed beforehand. For example, when it is defined that about100 mg of the formulation is sprayed through one-shot of the sprayoperation, the prefixed amount is 100 mg.

In the present invention, it is preferable that the formulation sprayedin the prefixed amount ±10% is 70 % or more, and more preferably 80% ormore.

The antiseptic agent defined herein includes, but are not limited to,benzalkonium chloride and benzethonium chloride. The preservativeincludes, but is not limited to, a paraben such as methylparaben andpropylparaben. Herein, the usual amount of an additive means an additiveamount which is permitted, for example, as the pharmaceutical approval,which is easily guessed with the amount of an approved pharmaceutical, astructure thereof, etc. by a skilled person.

The spray container for a gel formulation (upper-pressure-reliefairless-type spray container) used herein includes a container asexemplified in FIG. 1 of the attached drawings.

The spray container is an airless pump container which is operated asfollows:

removing the cap of the container; and

depressing the annular flange of the pump which is attached on the headof the container

to spray from the spraying outlet the content in the suction chamber ofthe pump which was already sucked from the container inside, andsimultaneously

to slide the body of slidable valve up, relating with the absorption asvacating the container inside, wherein the circumference of the body ofslidable valve is prepared so that the annular outer surface of the bodycan move like a seal closely contacting the inner surface of thecontainer.

A spray container having the above-mentioned mechanism has been alreadypublished as an airless pump container provided that it does not mentionthe use for nasal spray (JP-A-2003-212262). However, it has been desiredto reduce useless space which does not contribute to the spray operationto a maximum extent, and to make it possible to smoothly replace air inthe suction chamber with a formulation when charging the suctionchamber, as a (upper-pressure-relief airless-type) spray container forthe gel-type formulation like the present invention. Especially, it wasanticipated that the residual amount in the container at the time thatthe non-fluid gel-type formulation of the present invention was sprayedout would be more than that of a conventional formulation because of itsbad retention. Thus, the inventors have further improved theconventional airless spray container, i.e., setting a ring for reducinguseless space as shown in the right half plane of FIG. 2, and furtherhaving a certain tilt angle on the body of slidable valve which isordinarily an even face. Through the improvements, the inventors havefound that it is possible to easily remove air in the container andfurther to almost completely remove the dead volume by setting a ringhaving the same tilt angle to almost completely fit the faces betweenthe body of slidable valve and the ring at the time of spraying out.Thus, the present inventors have found a system which the residualamount can be very little at the time of spraying out. Furthermore, thespray container for a gel formulation (upper-pressure-reliefairless-type spray container) which is used in the present invention andhas the above properties as shown in FIGS. 1 and 2 can provide a precisespraying amount as an ordinary pharmaceutical. When the certain tiltangle of the body of slidable valve is small, there can retain anairspace in the shoulder part of the body of the container; while whenthe angle is big, there can retain an airspace in the lower part of theslidable valve; both are inconvenient. The angle is preferably 5-30°,more preferably 15-25°.

In addition, the spray container for a gel formulation(upper-pressure-relief airless-type spray container) used herein is nota system absorbing external air, and thus has a very useful property asa pharmaceutical preparation that it is hard to suffermicroorganism-contamination from external air. Therefore, the spraycontainer is a very useful administration system for nasal spray fromthe viewpoint of safety and production cost because it is not requiredto use any excessive antiseptic agent or preservative.

The spray angle of the spray container for administration in theinvention can be used setting in any or all angle between 0° and 360°.For example, the above-mentioned sprayable preparation for nasal spraycan be used so that the body position for administration (the angle ofpatient's head) and spray angle of the spray container foradministration can be varied as shown in FIG. 3 of the attacheddrawings. That is to say, the present preparation can be sprayed in anyangles: i.e., around 0° which is an available angle in a conventionalnasal spray, 45°-90° which is hard to be sprayed, and 180° which isimpossible to be sprayed.

In the present invention, when tilting patient's head backward and usingthe spray container in an angle of 65-180°, the turbinate (nasal meatus)is thought to be changed from parallel direction to vertical directionso that the formulation can be dispersed and adhered on the tip of theturbinate at first. And then, the formulation captured/adhered in theturbinate will be carried backward by means of gravity and ciliarymovement of ciliated cells covering a mucosa to spread in a wide area ofthe turbinate.

Therefore, the angle between the body position, for administration andthe spray angle of spray container for administration may be set in anyangle of 0°-180°, preferably 45°-180°, further preferably 65°-180°, mostpreferably around 1350 in which the turbinate (nasal meatus) is set in avertical direction, and it is the most advantageous to spread in a widearea of the turbinate. The body position may be selected from standingposition, sitting position, lying position on one's back, lying positionon one's side, etc., i.e. any position is available. The preparation fornasal spray of the invention can be used in any spray angle foradministration.

EXAMPLE

Hereinafter, the invention is illustrated based on examples andexperiments, but are not limited thereto. Some preparations of thepresent invention which were formulated with an actual activepharmaceutical ingredient were shown in the latter part hereof aspreparation examples, while for some physicochemical tests, thefollowing 9 kinds of gel-type skin/mucosa-adhesive preparations whichhad each different viscosity were prepared with some ingredientsmentioned below, without any active pharmaceutical ingredient, andsubjected to the following physicochemical tests.

In the following examples and experiments, each viscosity was measuredat 20° C. with a viscometer type C.

Examples 1-3 are gel formulations which are prepared by adding the sameamount of sodium chloride as a viscosity modulating agent to eachformulation without using any shearing force, which have viscosities of1000, 2000 and 3000 mPa·s, respectively. (The viscosities of Example 1-3which are prepared without adding sodium chloride as a viscositymodulating agent are 31000 mPa·s, 35000 mPa·s, and 36000 mPa·s,respectively.)

Examples 4-7 are gel formulations which are prepared with a shearingforce. To Examples 6 and 7 is further added sodium chloride as aviscosity modulating agent together with a shearing force. Eachviscosity of Examples 4-7 is adjusted to 2500 mPa·s. (The viscosity ofExample 4 which is prepared without using any shearing force is 23000mPa·s. The viscosity of Example 5 which is prepared without using anyshearing force and the viscosities of Example 6 and Example 7 which areprepared without using sodium chloride as a viscosity modulating agentand any shearing force are all 34000 mPa·s.)

Example 8 is a formulation having the same composition as Example 4-7,wherein the viscosity is adjusted to 2500 mPa·s with a viscositymodulating agent, without any shearing force. (The viscosity of Example8 which is prepared without adding sodium chloride as a viscositymodulating agent is 34000 mPa·s.)

A comparative example as a control formulation of Examples 4-8 wasprepared without using any viscosity modulating agent or any outsideshearing force, wherein the viscosity was 2500 mPa·s.

Quantity (%(w/w)) Ingredients Example 1 Example 2 Example 3 carboxyvinyl polymer  0.42  0.53  0.56 L-arginine  0.74  0.95 1.0 disodiumedetate  0.05  0.05  0.05 polysorbate 80 0.1 0.1 0.1 concentratedglycerin 1.0 1.0 1.0 sodium chloride 0.5 0.5 0.5 purified water 97.1996.87 96.79 Total 100% 100% 100% Detected viscosity 1000 mPa · s 2000mPa · s 3600 mPa · s Quantity (%(w/w)) Comparative Ingredients Example 4Example 5 Example 6 Example 7 Example 8 Example carboxy vinyl  0.25 0.50.5 0.5 0.5  0.085 polymer L-arginine 0.5 1.0 1.0 1.0 1.0 0.17 sodium ——  0.125  0.25 0.5 — chloride purified water 99.25 98.5   98.375 98.2598.0  99.745 Total 100% 100% 100% 100% 100% 100% Detected Adjustment ofviscosity: adjusting 2500 mPa · s 2500 mPa · s viscosity the viscosityto 2500 mPa · s by using shearing force, i.e., by rotating theformulation at 15,000 rpm under cooling in an intermittently-jet-stream-generating-type high-speed spinning-type emulsifying device (Type:CLM-0.8S).

The containers used for the tests are the following spray containerwhich can spray about 100 mg in one operation.

Container of the present invention: a spray container for a gelformulation (upper-pressure-relief airless-type spray container) (100mg-sprayable pump, charged amount: 5 g).

Control container (1): a spray container of a commercial preparationwhich has a double structure, wherein the inside structure is in amortal-form, characterized by minimizing the remaining amount in thecontainer (100 mg-pump, charged amount: 5 g).

Control container (2): a conventional spray container (100 mg-pump,charged amount: 5 g).

Tests for Remaining Amount in the Container, Amount Sprayed within thePrefixed Range, and Spray Frequency

About 5.0 g of each formulation of Example 1-Example 8 was exactlyweighed and put into the three kinds of spray containers: container ofthe invention, control container (1) and control container (2) whichwere weighed in the vacant state beforehand. The containers were tiltedat the angle between 0°-180° shown in Tables 1 and 2. The spray amountof every one-shot of the spray operation was measured by calculating theweight difference between before and after shot, and the measurement wasrepeated until the formulation was sprayed out almost completely. Table1 shows the result using the container of the invention, and Table 2shows using the control containers.

In addition, as a distribution (%) of the formulation put in thecontainer after spraying out,

the remains (%) in the container at the time that the spray operationwith the pump gets impossible,

“formulation (%) sprayed within 100±10 mg” which denotes the rate of thecumulative amount of the formulation sprayed in the range of theprefixed amount (100 mg)±10%, per the total amount of the formulation,and “formulation (%) sprayed outside 100±10 mg” which denotes the rateof the formulation sprayed outside the range were calculated using thefollowing formulas. The results are also shown in Tables 1 and 2.

Remains in the container (%)=Remains in the container (g)/Initial fillamount (g)×100

Formulation (%) sprayed within 100±10 mg=The cumulative amount (g) ofthe formulation sprayed in the range of 100±10 mg/Initial fill amount(g)×100

Formulation (%) sprayed outside 100±10 mg=The cumulative amount (g) ofthe formulation sprayed outside the range of 100±10 mg/Initial fillamount (g)×100

Furthermore, the frequency of the shots which could be sprayed in therange of 100±10 mg is shown therein.

TABLE 1 Test results using the container of the invention Distribution(%) of the formulation put in the container after spraying out CountFormulation Formulation of shots Spray Remains sprayed sprayed sprayedContainer angle for Viscosity in the within outside within typeadministration Formulation (mPa · s) container 100 ± 10 mg 100 ± 10 mg100 ± 10 mg Container  0° Example 1 1000 7.1 87.8 5.1 44 of the Example2 2000 7.2 87.6 5.2 44 invention Example 3 3600 7.3 87.7 5.0 44 Example4 2500 7.1 87.9 5.0 44 Example 5 2500 7.2 87.7 5.1 44 Example 6 2500 7.287.8 5.0 45 Example 7 2500 7.2 87.6 5.2 44 Example 8 2500 7.1 87.9 5.045 25° Example 2 2000 — — — — Example 7 2500 7.1 87.8 5.1 45 45° Example2 2000 7.1 87.7 5.2 44 Example 7 2500 7.2 87.6 5.2 44 65° Example 2 20007.1 87.4 5.5 44 Example 7 2500 7.1 87.7 5.2 45 90° Example 2 2000 7.187.8 5.1 44 Example 7 2500 7.2 87.5 5.3 44 180°  Example 2 2000 7.1 87.75.2 44 Example 7 2500 7.2 87.8 5.0 45

TABLE 2 Test results using control container (1) and control container(2) Distribution (%) of the formulation put in the container afterspraying out Count Formulation Formulation of shots Spray Remainssprayed sprayed sprayed Container angle for Viscosity in the withinoutside within type administration Formulation (mPa · s) container 100 ±10 mg 100 ± 10 mg 100 ± 10 mg Control 0° Example 1 1000 24.4 65.4 10.233 container Example 2 2000 27.7 61.0 11.3 31 (1) Example 3 3600 31.354.7 14.0 28 Example 4 2500 26.2 62.1 11.7 32 Example 5 2500 28.1 59.712.2 30 Example 6 2500 27.3 60.0 12.7 30 Example 7 2500 28.4 58.4 13.230 Example 8 2500 28.0 59.7 12.3 30 Control 0° Example 1 1000 28.5 55.116.4 28 container Example 2 2000 32.8 47.2 20.0 24 (2) Example 3 360038.6 39.2 22.2 20 Example 4 2500 30.9 50.5 18.6 26 Example 5 2500 31.649.2 19.2 25 Example 6 2500 31.8 48.1 20.1 24 Example 7 2500 32.7 47.320.1 24 Example 8 2500 34.5 46.8 18.7 24

When using the present system using the container of the presentinvention, the distribution rate (%) of the formulation put in thecontainer after spraying out could be almost constant even if theformulation is highly viscous, i.e. it is almost constant without beingaffected by the viscosity or the spray angle for administration. Theresults showed that the remains amount in the container were low (about7.1%), and the formulation amount sprayed within the prefixed range washigh (about 87.7 %). While, when using Control container (1) and Controlcontainer (2), the distribution rate was affected by the viscosity asshown in the following Table 2, i.e., the remains amount in thecontainers increased and the formulation amount sprayed within theprefixed range decreased as the viscosity rose.

Hereinafter, the results shown in the above Table 1 and Table 2 werere-constituted by classifying the results on the basis of the sprayangle for administration and the kind of the preparations, and there-constituted results are shown in Table 3-Table 8.

The results wherein the spray angle for administration is 0° aresummarized in Table 3, Table 4 and Table 5 which are classified on thebasis of each viscosity and each spray container. The results have shownthat the present system using the container of the invention is veryuseful. In addition, FIG. 4, FIG. 5 and FIG. 6 graphed on the basis ofthe results in Table 3-Table 5 show the relation between the viscosityand the stability regarding the sprayed amount comparing between eachspray container. These graphs also show that the present system isuseful.

TABLE 3 Distribution rate (%) of the formulation after spraying outwhich has viscosity (1000 mPa · s) in each spray container Distribution(%) of the formulation put in the container after spraying out CountFormulation Formulation of shots Spray Remains sprayed sprayed sprayedContainer angle for Viscosity in the within outside within typeadministration Formulation (mPa · s) container 100 ± 10 mg 100 ± 10 mg100 ± 10 mg Container 0° Example 1 1000 7.1 87.8 5.1 44 of the inventionControl Example 1 1000 24.4 65.4 10.2 33 container (1) Control Example 11000 28.5 55.1 16.4 28 container (2)

TABLE 4 Distribution rate (%) of the formulation after spraying outwhich has viscosity (2000 mPa · s) in each spray container Distribution(%) of the formulation put in the container after spraying out CountFormulation Formulation of shots Spray Remains sprayed sprayed sprayedContainer angle for Viscosity in the within outside within typeadministration Formulation (mPa · s) container 100 ± 10 mg 100 ± 10 mg100 ± 10 mg Container 0° Example 2 2000 7.2 87.6 5.2 44 of the inventionControl Example 2 2000 27.7 61.0 11.3 31 container (1) Control Example 22000 32.8 47.2 20.0 24 container (2)

TABLE 5 Distribution rate (%) of the formulation after spraying outwhich has viscosity (3600 mPa · s) in each spray container Distribution(%) of the formulation put in the container after spraying out CountFormulation Formulation of shots Spray Remains sprayed sprayed sprayedContainer angle for Viscosity in the within outside within typeadministration Formulation (mPa · s) container 100 ± 10 mg 100 ± 10 mg100 ± 10 mg Container 0° Example 3 3600 7.3 87.7 5.0 44 of the inventionControl Example 3 3600 31.3 54.7 14.0 28 container (1) Control Example 33600 38.6 39.2 22.2 20 container (2)

In addition, the results of the distribution (i) of the formulation putin the container after spraying out, wherein Example 2 or Example 7 isselected as a content of the preparation, are summarized in Table6-Table 11 which are classified on the basis of each spray angle foradministration and each spray container. The results have shown that thepresent system using the container of the invention has a low residualrate and enable a very stable spray in any spray angle. In addition,FIG. 7-FIG. 9 graphed on the basis of the results in Table 6-Table 8show the relation between the spray angle for administration and thestability regarding the sprayed amount comparing between each spraycontainer. These graphs show that it is only the system of the presentinvention to be able to use in a spray angle of 65° or 90°.

TABLE 6 Distribution rate (%) of the formulation after spraying outwhich has viscosity (2000 mPa · s) and spray angle (45°) in each spraycontainer Distribution (%) of the formulation put in the container afterspraying out Count Formulation Formulation of shots Spray Remainssprayed sprayed sprayed Container angle for Viscosity in the withinoutside within type administration Formulation (mPa · s) container 100 ±10 mg 100 ± 10 mg 100 ± 10 mg Container 45° Example 2 2000 7.1 87.7 5.244 of the invention Control Example 2 2000 35.7 48.5 15.8 25 container(1) Control Example 2 2000 40.3 34.3 25.4 18 container (2)

TABLE 7 Distribution rate (%) of the formulation after spraying outwhich has viscosity (2000 mPa · s) and spray angle (65°) in each spraycontainer Distribution (%) of the formulation put in the container afterspraying out Count Formulation Formulation of shots Spray Remainssprayed sprayed sprayed Container angle for Viscosity in the withinoutside within type administration Formulation (mPa · s) container 100 ±10 mg 100 ± 10 mg 100 ± 10 mg Container 65° Example 2 2000 7.1 87.4 5.544 of the invention Control Example 2 2000 60.7 9.4 29.9 5 container (1)Control Example 2 2000 72.8 0.0 27.2 0 container (2)

TABLE 8 Distribution rate (%) of the formulation after spraying outwhich has viscosity (2000 mPa · s) and spray angle (90°) in each spraycontainer Distribution (%) of the formulation put in the container afterspraying out Count Formulation Formulation of shots Spray Remainssprayed sprayed sprayed Container angle for Viscosity in the withinoutside within type administration Formulation (mPa · s) container 100 ±10 mg 100 ± 10 mg 100 ± 10 mg Container 90° Example 2 2000 7.1 87.8 5.144 of the invention Control Example 2 2000 70.7 0.0 29.3 0 container (1)Control Example 2 2000 81.4 0.0 18.6 0 container (2)

TABLE 9 Distribution rate (%) of the formulation after spraying outwhich has viscosity (2500 mPa · s) and spray angle (45°) in each spraycontainer Distribution (%) of the formulation put in the container afterspraying out Count Formulation Formulation of shots Spray Remainssprayed sprayed sprayed Container angle for Viscosity in the withinoutside within type administration Formulation (mPa · s) container 100 ±10 mg 100 ± 10 mg 100 ± 10 mg Container 45° Example 7 2500 7.1 87.9 5.045 of the invention Control Example 7 2500 36.1 46.8 17.1 24 container(1) Control Example 7 2500 47.2 30.5 22.3 15 container (2)

TABLE 10 Distribution rate (%) of the formulation after spraying outwhich has viscosity (2500 mPa · s) and spray angle (65°) in each spraycontainer Distribution (%) of the formulation put in the container afterspraying out Count Formulation Formulation of shots Spray Remainssprayed sprayed sprayed Container angle for Viscosity in the withinoutside within type administration Formulation (mPa · s) container 100 ±10 mg 100 ± 10 mg 100 ± 10 mg Container 65° Example 7 2500 7.2 87.5 5.344 of the invention Control Example 7 2500 62.9 8.1 29.0 4 container (1)Control Example 7 2500 79.2 0.0 20.8 0 container (2)

TABLE 11 Distribution rate (%) of the formulation after spraying outwhich has viscosity (2500 mPa · s) and spray angle (90°) in each spraycontainer Distribution (%) of the formulation put in the container afterspraying out Count Formulation Formulation of shots Spray Remainssprayed sprayed sprayed Container angle for Viscosity in the withinoutside within type administration Formulation (mPa · s) container 100 ±10 mg 100 ± 10 mg 100 ± 10 mg Container 90° Example 7 2500 7.1 87.8 5.145 of the invention Control Example 7 2500 77.5 0.0 22.5 0 container (1)Control Example 7 2500 84.5 0.0 15.5 0 container (2)

Comparison of Mean Particle Size

Each mean particle size of the gel-type skin/mucosa-adhesivepreparations of the present invention and other gel-typeskin/mucosa-adhesive preparations which were sprayed was measured with aparticle size analyzer which uses a laser light scattering method andanalyzed (Table 12). The containers used herein were all the same spraycontainer for a gel formulation (upper-pressure-relief airless-typespray container).

It has been found that the sprayed gel-type skin/mucosa-adhesivepreparation of the present invention has a small particle size,especially an ideal particle size (50-100 μm) as a drug preparation forintranasal administration, though it is highly viscous.

TABLE 12 Comparison of mean particle size of each formulation Sprayangle of Mean Viscosity spray container for particle Formulation (mPa ·s) administration size (μm) Example 1 1000 0° 74.8 Example 2 2000 0°75.3 Example 3 3600 0° 87.5 Example 4 2500 0° 71.1 Example 5 2500 0°233.4 Example 6 2500 0° 69.8 Example 7 2500 0° 66.6 Example 8 2500 0°77.3 Comparative example 2500 0° 77.5 hydroxypropyl cellulose 1000 0°294.1 hydroxypropyl cellulose 2000 0° 531.6 carmellose sodium 400 0°88.4 carmellose sodium 1000 0° 192.5 carmellose sodium 2000 0° 254.9

Comparison of Viscosity Retained Through Spraying Operation

Each viscosity of the gel-type skin/mucosa-adhesive preparation of thepresent invention and other gel-type skin/mucosa-adhesive preparation atthe time before/after spraying was measured and the variation due tospraying was compared each other (Table 13). The containers used hereinwere all the same spray container for a gel formulation(upper-pressure-relief airless-type spray container). It has been foundthat it is only the gel-type skin/mucosa-adhesive-preparation of thepresent invention to exhibit a very high viscosity retention rate.Especially, in Examples 4-7 which were prepared by adding a shearingforce to adjust the viscosity, there was no variation of the viscosityat the time before/after spraying, and it was a very high viscosityretention rate.

TABLE 13 Comparison of viscosity retained through spraying operationViscosity Viscosity Viscosity before spraying after spraying retentionrate Formulation (mPa · s) (mPa · s) (%) Example 1 1000 850 85.0 Example2 2000 1750 87.5 Example 3 3600 3200 88.9 Example 4 2500 2500 100.0Example 5 2500 2500 100.0 Example 6 2500 2500 100.0 Example 7 2500 2500100.0 Example 8 2500 2180 87.2 Comparative example 2500 1010 40.4hydroxypropyl cellulose 1000 55 5.5 hydroxypropyl cellulose 2000 120 6.0carmellose sodium 400 1 0.3 carmellose sodium 1000 18 1.8 carmellosesodium 2000 75 3.8

Comparison of Spray Spreading-Angle and Spray Spread Through SprayingOperation

Using each of the above-prepared gel-type skin/mucosa-adhesivepreparations which have different viscosities and are prepared viadifferent processes, spray spreading-angle and spray spread thereof weremeasured, and compared each other (Table 14). The containers used hereinwere all the same spray container for a gel formulation(upper-pressure-relief airless-type spray container).

Each spray spreading-angle was not affected by the difference of eachviscosity (see, for example, the comparison between Examples 1-3). InExamples 4-7 which were gel-type mucosa-adhesive preparations preparedby adding a shearing force to adjust the viscosity, each sprayspreading-angle tended to be narrowed. Amongst these examples, Example 6and Example 7 comprising sodium chloride as a viscosity modulating agenttended to exhibit a wider spray spreading-angle compared with Example 5which did not comprise sodium chloride.

In addition, each spray spread was also affected by the addition of ashearing force. That is to say, it has been found that in Examples 1-3and Example 8 to which a shearing force was not added, each spray spreadwas localized at the periphery, while, in Examples 4-7 to which ashearing force was added, each spray spread was uniform (see FIGS.10-13).

From these findings, the gel-type skin/mucosa-adhesive preparation ofthe present invention can be controlled by adjusting the viscosity byadding a viscosity modulating agent and an outside shearing force, sothat the spray spreading-angle from a spray container, and the sprayspread can meet a purpose. For example, when the active pharmaceuticalingredient is an ionic compound and is in a solution state, it ispossible to adjust the spray spreading-angle from a spray container anduniformalize the spray spread by adding only an outside shearing force,because the ingredient works as a viscosity modulating agent.

TABLE 14 Comparison of spray spreading-angle and spray spread throughspraying operation Spray spread Spray Reference Formulationspreading-angle Result figure Example 1 57.8 localized at — theperiphery Example 2 57.3 localized at — the periphery Example 3 56.0localized at — the periphery Example 4 46.4 sprayed in — uniformityExample 5 18.8 sprayed in FIG. 10 uniformity Example 6 40.5 sprayed inFIG. 11 uniformity Example 7 45.5 sprayed in FIG. 12 uniformity Example8 57.5 localized at FIG. 13 the peripheryComparison of Viscosity of the Formulation Varied with Prepared NasalDischarge

Using the following ingredients, gel-type skin/mucosa-adhesivepreparations comprising gellan gum were prepared. The abovepreparations, Example 4-Example 8, and Comparative example weresubjected to a comparison-experiment about the viscosity variation usinga prepared nasal discharge (the composition is shown below).

The prepared nasal discharge is a liquid preparation comprising similarions and similar concentration thereof to human nasal discharge. Theprepared nasal discharge was added to each preparations, and themixtures were made to be uniformalized. After about 5 minutes, eachviscosity was measured. (The amount of the prepared nasal dischargeadded was shown as an amount added to 10 g of each preparation).

Quantity (%(w/w)) Ingredients Example 9 Example 10 carboxy vinyl polymer0.15 0.35 gellan gum 0.15 0.15 L-arginine 0.30 0.70 sodium chloride —0.27 purified water 99.40 98.53 Total 100% 100% Detected viscosity 2500mPa · s 2500 mPa · s

[Composition of Prepared Nasal Discharge]

NaCl 6.81 g KCl 1.91 g CaCl₂•2H₂O 0.59 g MgCl₂•6H₂O 0.13 g Total 1000 mL

The above “prepared nasal discharge” is prepared based on thecomposition described in the Japanese Society of Public Health (MorioSABURI, et al., Vol. 39, No. 6, P 341-P 346, 1992).

The variation in the viscosity of each gel-type mucosa-adhesivepreparation of the present invention by adding a prepared nasaldischarge is shown in FIG. 14. All the containers used in the experimentwere the same spray container for a gel formulation(upper-pressure-relief airless-type spray container). In Comparativeexample wherein the viscosity was not adjusted by adding a viscositymodulating agent or an outside shearing force, it was observed that theviscosity was markedly decreased by adding the prepared nasal discharge.While, in Examples 4-10 wherein the viscosity was adjusted with eitherof the above-mentioned treatments, the lowering of the viscosity couldbe stopped to a high degree. Especially, it should be noted thatExamples 9 and 10 which contain gellan gum were more resistant to beaffected at the viscosity change by increasing the added prepared nasaldischarge than the other Examples which do not contain gellan gum.

Comparison of Stability Against Microorganism

0.2% Gellan gum solution was heat-sterilized to be a content of thepreparation. The spray container for a gel formulation(upper-pressure-relief airless-type spray container) and Controlcontainer (2) which were EOG-sterilized were charged with 5 g of thecontent. 2.5 g of the content was sprayed from each container until theremaining amount of the content in each container should be 50 %, andeach container was stored in an incubator at 37° C., or at roomtemperature. Each amount of microorganism was observed over time, andthe stability of each container against microorganism was compared eachother (Table 15). It was indicated that the stability againstmicroorganism using the spray container for a gel formulation of thepresent invention is superior to that of the conventional container fornasal spray.

TABLE 15 Comparison of stability against microorganism FormulationContainer In incubator at 37° C. At room temperature 0.2% gellanContainer No change over time. No change over time. gum solution of theinvention 0.2% gellan Control Microorganism colony Microorganism colonygum solution Container was visibly observed was visibly observed (2)after 3 weeks. after 7 weeks.

Comparison of Intranasal Retention Using Saccharin Preparation

The preparation prepared by adding saccharin sodium (having sweet taste)to the formulation of Example 2 wherein the concentration of saccharinsodium is 0.5 %, and 0.5% saccharin sodium solution in water werenasally administered (each one shot to both nostrils, total: 200 mg) tosubjects (3 subjects: A, B, C) in a variety of angles using nasal spraycontainer for a gel formulation (upper-pressure-relief airless-typespray container) equipped with a pump which can be sprayed in 100 mg pera shot. A certain period after administration, the head of each subjectwas set in a vertical direction. The time that was needed from theadministration until the time when a subject begins to taste sweet ineach trial was recorded and compared each other (Table 16-Table 19). Inall cases, the gel-type skin/mucosa-adhesive preparation of Example 2needed even more time than the normal non-gel type solution for eachsubject to begin to taste sweet, thus it was indicated that theintranasal retention of the gel-type preparation was sufficiently high.

TABLE 16 Comparison of intranasal retention using saccharin preparation(The case that the head was set in a vertical direction shortly afterthe administration.) Preparation comprising Spray 0.5% saccharin 0.5%saccharin Na angle Na of Example 2 solution in water  0° A 32 minAverage A 3 min Average 10 sec 15 sec B 37 min 37 min B 4 min 4 min 30sec 12 sec 30 sec 22 sec C 41 min C 5 min 55 sec 20 sec 25° A 29 minAverage A 5 min Average 45 sec 10 sec B 39 min 35 min B 3 min 3 min 45sec 57 sec 35 sec 37 sec C 38 min C 2 min 20 sec 05 sec 45° A 28 minAverage A 4 min Average 20 sec 15 sec B 36 min 34 min B 2 min 3 min 35sec 40 sec 30 sec 22 sec C 39 min C 3 min 05 sec 20 sec 65° A 31 minAverage A 2 min Average 15 sec 20 sec B 35 min 35 min B 1 min 1 min 05sec 58 sec 45 sec 48 sec C 41 min C 1 min 35 sec 20 sec 90° A 33 minAverage A 45 sec Average 25 sec B 39 min 39 min B 15 sec 23 sec 25 sec35 sec C 45 min C 10 sec 55 sec

TABLE 17 Comparison of intranasal retention using saccharin preparation(The case that the head was set in a vertical direction 15 sec. afterthe administration.) Preparation comprising Spray 0.5% saccharin 0.5%saccharin Na angle Na of Example 2 solution in water 65° A 36 minAverage A 55 sec Average 05 sec B 39 min 39 min B 1 min 1 min 05 sec 50sec 15 sec 02 sec C 44 min C 55 sec 20 sec 90° A 42 min Average A 15 secAverage 20 sec B 33 min 38 min B 10 sec 12 sec 10 sec 07 sec C 38 min C5 sec 50 sec

TABLE 18 Comparison of intranasal retention using saccharin preparation(The case that the head was set in a vertical direction 30 sec. after,the administration.) Preparation comprising Spray 0.5% saccharin 0.5%saccharin Na angle Na of Example 2 solution in water 65° A 35 minAverage A 55 sec Average 10 sec B 40 min 38 min B 15 sec 27 sec 55 sec37 sec C 39 min C 10 sec 45 sec 90° A 42 min Average A  5 sec Average 30sec B 35 min 40 min B 10 sec  7 sec 45 sec 22 sec C 42 min C  5 sec 50sec

TABLE 19 Comparison of intranasal retention using saccharin preparation(The case of the administration in lying position on one's back (135°)and holding the position for 5 min) Preparation comprising Spray 0.5%saccharin 0.5% saccharin Na angle Na of Example 2 solution in water 135°A 45 min Average A 5 sec Average 05 sec B 29 min 36 min B 5 sec 5 sec 50sec 42 sec C 35 min C 5 sec 10 sec

Hereinafter, some examples that were actually prepared using an activepharmaceutical ingredient are described as a formulation example. But,the present invention should not be limited thereto.

Preparation example 01 (Example 11): Drug formulation applicable tonasal cavity comprising oxymetazoline Ingredients Quantity (%(w/w))oxymetazoline hydrochloride 0.05 carboxy vinyl polymer 0.40 L-arginine0.30 benzalkonium chloride 0.01 purified water 99.24 Total 100%

-   -   Adjustment of viscosity: adjusting the viscosity to 1000 mPa·s        by using shearing force, i.e., by rotating the formulation at        15,000 rpm under cooling in an        intermittently-jet-stream-generating-type high-speed        spinning-type emulsifying device (Type: CLM-0.8S).

Preparation example 02 (Example 12): Drug formulation applicable tonasal cavity comprising tetrahydrozoline Ingredients Quantity (% (w/w))tetrahydrozoline hydrochloride 0.10 chlorpheniramine maleate 0.50lidocaine 0.30 glycyrrhizinate dipotassium 0.20 benzethonium chloride0.01 carboxy vinyl polymer 0.55 L-arginine 0.35 sodium hydroxide 0.05macrogol 400 3.00 purified water 94.94 Total 100%

-   -   Adjustment of viscosity: adjusting the viscosity to 2000 mPa·s        by using shearing force, i.e., by rotating the formulation at        20,000 rpm under cooling in an        intermittently-jet-stream-generating-type high-speed        spinning-type emulsifying device (Type: CLM-0.8S).

Preparation example 03 (Example 13): Drug formulation applicable tonasal cavity comprising fluticasone propionate Ingredients Quantity (%(w/w)) fluticasone propionate 0.51 carboxy vinyl polymer 0.53 L-arginine0.95 polysorbate 80 0.10 concentrated glycerin 2.00 sodium chloride0.125 purified water 95.785 Total 100%

-   -   Adjustment of viscosity: adjusting the viscosity to 2200 mPa·s        by using shearing force, i.e., by rotating the formulation at        15,000 rpm under cooling in an        intermittently-jet-stream-generating-type high-speed        spinning-type emulsifying device (Type: CLM-0.8S).

Preparation example 04 (Example 14): Drug formulation applicable tonasal cavity comprising fluticasone propionate Ingredients Quantity (%(w/w)) fluticasone propionate 0.51 carboxy vinyl polymer 0.35 gellan gum0.15 L-arginine 0.55 polysorbate 80 0.10 concentrated glycerin 1.00sodium chloride 0.25 purified water 97.09 Total 100%

Preparation example 05 (Example 15): Drug formulation applicable tonasal cavity comprising mometasone furoate Ingredients Quantity (%(w/w)) mometasone furoate 0.50 carboxy vinyl polymer 0.56 L-arginine1.00 polysorbate 80 0.10 concentrated glycerin 2.00 sodium chloride 0.25purified water 95.59 Total 100%

-   -   Adjustment of viscosity: adjusting the viscosity to 2500 mPa·s        by using shearing force, i.e., by rotating the formulation at        15,000 rpm under cooling in an        intermittently-jet-stream-generating-type high-speed        spinning-type emulsifying device (Type: CLM-0.8S).

Preparation example 06 (Example 16): Drug formulation applicable tonasal cavity comprising insulin (50 U/g) Ingredients Quantity (% (w/w))insulin 0.1887 carboxy vinyl polymer 0.30 L-arginine 0.55 concentratedglycerin 1.00 sodium chloride 0.125 purified water 97.8363 Total 100%

-   -   Insulin is mixed in 10 parts of purified water by weight. While,        the other ingredients are mixed and the viscosity of the mixture        is adjusted by the means as mentioned below, and then the        insulin solution is added to the mixture and the resulting        mixture is stirred to be uniform.    -   Adjustment of viscosity: adjusting the viscosity to 750 mPa·s by        using shearing force, i.e., by rotating the formulation at        15,000 rpm under cooling in an        intermittently-jet-stream-generating-type high-speed        spinning-type emulsifying device (Type: CLM-0.8S).

Preparation example 07 (Example 17): Drug formulation applicable tonasal cavity comprising levocabastine Ingredients Quantity (% (w/w))levocabastine hydrochloride 0.027 carboxy vinyl polymer 0.50 L-arginine1.05 sucrose fatty acid ester 0.10 concentrated glycerin 2.00 sodiumchloride 0.125 purified water 96.198 Total 100%

-   -   Adjustment of viscosity: adjusting the viscosity to 2700 mPa·s        by using shearing force, i.e., by rotating the formulation at        20,000 rpm under cooling in an        intermittently-jet-stream-generating-type high-speed        spinning-type emulsifying device (Type: CLM-0.8S).

Preparation example 08 (Example 18): Drug formulation applicable tonasal cavity comprising cromolyn sodium Ingredients Quantity (% (w/w))cromolyn sodium 1.00 chlorpheniramine maleate 0.25 naphazolinehydrochloride 0.025 carboxy vinyl polymer 0.65 L-arginine 0.65 sodiumchloride 0.05 disodium edetate 0.10 benzalkonium chloride 0.01 purifiedwater 97.265 Total 100%

-   -   Adjustment of viscosity: adjusting the viscosity to 2000 mPa·s        by using shearing force, i.e., by rotating the formulation at        15,000 rpm under cooling in an        intermittently-jet-stream-generating-type high-speed        spinning-type emulsifying device (Type: CLM-0.8S).

Preparation example 09 (Example 19): Drug formulation applicable tonasal cavity comprising fentanyl Ingredients Quantity (% (w/w)) fentanylcitrate 0.157 carboxy vinyl polymer 0.55 L-arginine 0.50 polysorbate 800.10 concentrated glycerin 1.00 benzalkonium chloride 0.01 sodiumchloride 0.125 purified water 97.558 Total 100%

-   -   Adjustment of viscosity: adjusting the viscosity to 2500 mPa·s        by using shearing force, i.e., by rotating the formulation at        15,000 rpm under cooling in an        intermittently-jet-stream-generating-type high-speed        spinning-type emulsifying device (Type: CLM-0.8S).

Preparation example 10 (Example 20): Drug formulation applicable tonasal cavity comprising fentanyl Ingredients Quantity (% (w/w)) fentanylcitrate 0.157 carboxy vinyl polymer 0.175 gellan gum 0.175 L-arginine0.155 polysorbate 80 0.10 concentrated glycerin 1.00 benzalkoniumchloride 0.01 purified water 98.228 Total 100%

Preparation example 11 (Example 21): Drug formulation applicable tonasal cavity comprising fentanyl Ingredients Quantity (% (w/w)) fentanylcitrate 0.628 carboxy vinyl polymer 0.55 L-arginine 0.50 polysorbate 800.10 concentrated glycerin 1.00 benzalkonium chloride 0.01 purifiedwater 97.212 Total 100%

-   -   Adjustment of viscosity: adjusting the viscosity to 2500 mPa·s        by using shearing force, i.e., by rotating the formulation at        15,000 rpm under cooling in an        intermittently-jet-stream-generating-type high-speed        spinning-type emulsifying device (Type: CLM-0.8S).

Preparation example 12 (Example 22): Drug formulation applicable tonasal cavity comprising sumatriptan Ingredients Quantity (% (w/w))sumatriptan 2.00 carboxy vinyl polymer 0.50 L-arginine 0.50 polysorbate80 0.10 concentrated glycerin 1.00 benzalkonium chloride 0.01 purifiedwater 95.89 Total 100%

-   -   Adjustment of viscosity: adjusting the viscosity to 2500 m·Pas        by using shearing force, i.e., by rotating the formulation at        15,000 rpm under cooling in an        intermittently-jet-stream-generating-type high-speed        spinning-type emulsifying device (Type: CLM-0.8S).

Preparation example 13 (Example 23): Drug formulation applicable tonasal cavity comprising buserelin Ingredients Quantity (% (w/w))buserelin acetate 0.1575 carboxy vinyl polymer 0.50 L-arginine 0.45sodium chloride 0.25 concentrated glycerin 1.50 benzalkonium chloride0.01 purified water 97.1325 Total 100%

-   -   Buserelin acetate is mixed in 10 parts of purified water by        weight. While, the other ingredients are mixed and the viscosity        of the mixture is adjusted by the means as mentioned below, and        then the buserelin acetate solution is added to the mixture and        the resulting mixture is stirred to be uniform.    -   Adjustment of viscosity: adjusting the viscosity to 1500 mPa·s        by using shearing force, i.e., by rotating the formulation at        15,000 rpm under cooling in an        intermittently-jet-stream-generating-type high-speed        spinning-type emulsifying device (Type: CLM-0.8S).

Preparation example 14 (Example 24): Drug formulation applicable tonasal cavity comprising desmopressin Ingredients Quantity (% (w/w))desmopressin acetate 0.01 carboxy vinyl polymer 0.50 L-arginine 0.40sodium chloride 0.125 concentrated glycerin 1.50 benzalkonium chloride0.01 purified water 97.455 Total 100%

-   -   Desmopressin acetate is mixed in 10 parts of purified water by        weight. While, the other ingredients are mixed and the viscosity        of the mixture is adjusted by the means as mentioned below, and        then the desmopressin acetate solution is added to the mixture        and the resulting mixture is stirred to be uniform.    -   Adjustment of viscosity: adjusting the viscosity to 2000 mPa·s        by using shearing force, i.e., by rotating the formulation at        15,000 rpm under cooling in an        intermittently-jet-stream-generating-type high-speed        spinning-type emulsifying device (Type: CLM-0.8S).

Preparation example 15 (Example 25): Drug formulation applicable to skincomprising loxoprofen sodium Ingredients Quantity (% (w/w)) loxoprofensodium 1.134 carboxy vinyl polymer 1.00 triethanolamine 1.30 ethanol20.00 1,3-butylene glycol 5.00 purified water 71.566 Total 100%

-   -   Adjustment of viscosity: adjusting the viscosity to 3500 mPa·s        by using shearing force, i.e., by rotating the formulation at        15,000 rpm under cooling in an        intermittently-jet-stream-generating-type high-speed        spinning-type emulsifying device (Type: CLM-0.8S).

Preparation example 16 (Example 26): Drug formulation applicable to skincomprising loxoprofen sodium Ingredients Quantity (% (w/w)) loxoprofensodium 1.134 N-methyl-2-pyrrolidone 2.50 carboxy vinyl polymer 1.00octyldodecanol 10.00 polyoxyl 40 stearate 1.00 glyceryl monostearate1.00 sodium hydroxide 0.40 1,3-butylene glycol 5.00 purified water77.966 Total 100%

-   -   Adjustment of viscosity: adjusting the viscosity to 3000 mPa·s        by using shearing force, i.e., by rotating the formulation at        15,000 rpm under cooling in an        intermittently-jet-stream-generating-type high-speed        spinning-type emulsifying device (Type: CLM-0.8S).

Preparation example 17 (Example 27): Drug formulation applicable to skincomprising chlorpheniramine maleate Ingredients Quantity (% (w/w))chlorpheniramine maleate 1.00 lidocaine 0.50 l-menthol 5.00 dl-camphor2.00 carboxy vinyl polymer 1.20 triethanolamine 1.68 ethanol 50.001,3-butylene glycol 10.00 purified water 28.62 Total 100%

-   -   Adjustment of viscosity: adjusting the viscosity to 5000 mPa·s        by using shearing force, i.e., by rotating the formulation at        15,000 rpm under cooling in an        intermittently-jet-stream-generating-type high-speed        spinning-type emulsifying device (Type: CLM-0.8S).

Preparation example 18 (Example 28): Drug formulation applicable to skincomprising acyclovir Ingredients Quantity (% (w/w)) acyclovir 5.00polysorbate 80 1.00 carboxy vinyl polymer 1.20 octyldodecanol 5.00polyoxyl 40 stearate 0.50 glyceryl monostearate 0.50 L-arginine 0.751,3-butylene glycol 5.00 purified water 81.05 Total 100%

-   -   Adjustment of viscosity: adjusting the viscosity to 2500 mPa·s        by using shearing force, i.e., by rotating the formulation at        20,000 rpm under cooling in an        intermittently-jet-stream-generating-type high-speed        spinning-type emulsifying device (Type: CLM-0.8S).

Preparation example 19 (Example 29): Drug formulation applicable to skincomprising lidocaine Ingredients Quantity (% (w/w)) lidocaine 7.00carboxy vinyl polymer 1.20 octyldodecanol 10.00 polyoxyl 40 stearate1.00 glyceryl monostearate 1.00 sodium hydroxide 0.48 1,3-butyleneglycol 5.00 purified water 74.32 Total 100%

-   -   Adjustment of viscosity: adjusting the viscosity to 3500 mPa·s        by using shearing force, i.e., by rotating the formulation-at        15,000 rpm under cooling in an        intermittently-jet-stream-generating-type high-speed        spinning-type emulsifying device (Type: CLM-0.8S).

Preparation example 20 (Example 30): Drug formulation applicable to skincomprising terbinafine Ingredients Quantity (% (w/w)) terbinafinehydrochloride 1.00 crotamiton 5.00 carboxy vinyl polymer 0.60octyldodecanol 5.00 polyoxyl 40 stearate 0.50 glyceryl monostearate 0.50sodium hydroxide 0.40 1,3-butylene glycol 5.00 purified water 82.00Total 100%

-   -   Adjustment of viscosity: adjusting the viscosity to 3000 mPa·s        by using shearing force, i.e., by rotating the formulation at        15,000 rpm under cooling in an        intermittently-jet-stream-generating-type high-speed        spinning-type emulsifying device (Type: CLM-0.8S).

Preparation example 21 (Example 31): Drug formulation applicable to skincomprising lanoconazole Quantity Ingredients (% (w/w)) lanoconazole 1.0crotamiton 5.0 polyoxyethylene hydrogenated castor oil 40 1.0 carboxyvinyl polymer 1.0 triethanolamine 1.0 ethanol 55.0 1,3-butylene glycol10.0 purified water 26.0 Total 100%

-   -   Adjustment of viscosity: adjusting the viscosity to 3000 mPa·s        by using shearing force, i.e., by rotating the formulation at        10,000 rpm under cooling in an        intermittently-jet-stream-generating-type high-speed        spinning-type emulsifying device (Type: CLM-0.8S).

Preparation example 22 (Example 32): Drug formulation applicable to skincomprising lanoconazole Ingredients Quantity (% (w/w)) lanoconazole 1.00crotamiton 5.00 carboxy vinyl polymer 1.00 octyldodecanol 10.00 polyoxyl40 stearate 0.50 glyceryl monostearate 0.50 sodium hydroxide 0.401,3-butylene glycol 5.00 purified water 76.60 Total 100%

-   -   Adjustment of viscosity: adjusting the viscosity to 3500 mPa·s        by using shearing force, i.e., by rotating the formulation at        15,000 rpm under cooling in an        intermittently-jet-stream-generating-type high-speed        spinning-type emulsifying device (Type: CLM-0.8S).

Preparation example 23 (Example 33): Drug formulation applicable to skincomprising betamethasone butyrate propionate Ingredients Quantity (%(w/w)) betamethasone butyrate propionate 0.05 crotamiton 5.00 carboxyvinyl polymer 1.00 octyldodecanol 10.00 macrogol 400 5.00polyoxylpolyoxyl 45 stearate 0.50 glyceryl monostearate 0.50 sodiumhydroxide 0.25 disodium edetate 0.01 purified water 77.69 Total 100%

-   -   Adjustment of viscosity: adjusting the viscosity to 4500 mPa·s        by using shearing force, i.e., by rotating the formulation at        20,000 rpm under cooling in an        intermittently-jet-stream-generating-type high-speed        spinning-type emulsifying device (Type: CLM-0.8S).

Preparation example 24 (Example 34): Drug formulation applicable to skincomprising maxacalcitol Ingredients Quantity (% (w/w)) maxacalcitol0.0025 carboxy vinyl polymer 0.85 octyldodecanol 10.00 concentratedglycerin 5.00 polyoxyl 45 stearate 0.50 glyceryl monostearate 0.50sodium hydroxide 0.25 disodium edetate 0.005 purified water 82.8925Total 100%

-   -   Adjustment of viscosity: adjusting the viscosity to 3000 m·Pas        by using shearing force, i.e., by rotating the formulation at        20,000 rpm under cooling in an        intermittently-jet-stream-generating-type high-speed        spinning-type emulsifying device (Type: CLM-0.8S).

Preparation example 25 (Example 35): Drug formulation applicable to thesurround of anus comprising prednisolone Ingredients Quantity (% (w/w))prednisolone acetate 0.10 dibucaine 0.50 benzalkonium chloride 0.10l-menthol 0.10 polysorbate 80 1.00 carboxy vinyl polymer 0.95 L-arginine0.35 disodium edetate 0.05 purified water 96.85 Total 100%

-   -   Adjustment of viscosity: adjusting the viscosity to 4000 mPa·s        by using shearing force, i.e., by rotating the formulation at        15,000, rpm under cooling in an        intermittently-jet-stream-generating-type high-speed        spinning-type emulsifying device (Type: CLM-0.8S).

Preparation example 26 (Example 36): Drug formulation applicable to thesurround of anus comprising diflucortolone valerate Ingredients Quantity(% (w/w)) diflucortolone valerate 0.01 lidocaine 2.00 carboxy vinylpolymer 0.85 L-arginine 0.55 octyldodecanol 5.00 polysorbate 80 1.00polyoxyl 45 stearate 1.00 glyceryl monostearate 1.00 purified water88.59 Total 100%

-   -   Adjustment of viscosity: adjusting the viscosity to 3000 mPa·s        by using shearing force, i.e., by rotating the formulation at        15,000 rpm under cooling in an        intermittently-jet-stream-generating-type high-speed        spinning-type emulsifying device (Type: CLM-0.8S).

Preparation example 27 (Example 37): Drug formulation applicable toscalp comprising minoxidil Ingredients Quantity (% (w/w)) minoxidil 1.00carboxy vinyl polymer 0.50 triethanolamine 0.50 ethanol 55.001,3-butylene glycol 10.00 purified water 33.00 Total 100%

-   -   Adjustment of viscosity: adjusting the viscosity to 4000 mPa·s        by using shearing force, i.e., by rotating the formulation at        20,000 rpm under cooling in an        intermittently-jet-stream-generating-type high-speed        spinning-type emulsifying device (Type: CLM-0.8S).

Preparation example 28 (Example 38): Drug formulation for ophthalmicapplication comprising ketotifen Ingredients Quantity (% (w/w))ketotifen fumarate 0.069 polysorbate 80 0.005 carboxy vinyl polymer 0.25L-arginine 0.20 concentrated glycerin 1.00 disodium edetate 0.005benzalkonium chloride 0.005 purified water 98.466 Total 100%

-   -   Adjustment of viscosity: adjusting the viscosity to 100 mPa·s by        using shearing force, i.e., by rotating the formulation at        15,000 rpm under cooling in an        intermittently-jet-stream-generating-type high-speed        spinning-type emulsifying device (Type: CLM-0.8S).

Preparation example 29 (Example 39): Drug formulation for oralapplication comprising triamcinolone acetonide Ingredients Quantity (%(w/w)) triamcinolone acetonide 0.025 polysorbate 80 0.050 carboxy vinylpolymer 0.50 L-arginine 0.45 concentrated glycerin 1.00 disodium edetate0.01 benzalkonium chloride 0.01 purified water 97.955 Total 100%

-   -   Adjustment of viscosity: adjusting the viscosity to 4000 mPa·s        by using shearing force, i.e., by rotating the formulation at        20,000 rpm under cooling in an        intermittently-jet-stream-generating-type high-speed        spinning-type emulsifying device (Type: CLM-0.8S).

Preparation example 30 (Example 40): Veterinary drug formulationapplicable to body comprising orbifloxacin Ingredients Quantity (%(w/w)) orbifloxacin 1.00 miconazole nitrate 1.00 triamcinolone acetonide0.10 crotamiton 5.00 concentrated glycerin 5.00 carboxy vinyl polymer0.64 octyldodecanol 10.00 polyoxyl 45 stearate 0.50 glycerylmonostearate 0.50 sodium hydroxide 0.10 disodium edetate 0.005 purifiedwater 76.155 Total 100%

-   -   Adjustment of viscosity: adjusting the viscosity to 5000 mPa·s        by using shearing force, i.e., by rotating the formulation at        20,000 rpm under cooling in an        intermittently-jet-stream-generating-type high-speed        spinning-type emulsifying device (Type: CLM-0.8S).

Preparation example 31 (Example 41): Veterinary drug formulationapplicable to ear comprising orbifloxacin Ingredients Quantity (% (w/w))orbifloxacin 1.00 miconazole nitrate 1.00 crotamiton 5.00 concentratedglycerin 5.00 carboxy vinyl polymer 0.55 octyldodecanol 10.00 polyoxyl45 stearate 0.50 glyceryl monostearate 0.50 sodium hydroxide 0.086disodium edetate 0.005 purified water 76.359 Total 100%

-   -   Adjustment of viscosity: adjusting the viscosity to 500 mPa·s by        using shearing force, i.e., by rotating the formulation at        20,000 rpm under cooling in an        intermittently-jet-stream-generating-type high-speed        spinning-type emulsifying device (Type: CLM-0.8S).

INDUSTRIAL APPLICABILITY

As mentioned above, the sprayable gel-type skin/mucosa-adhesivepreparation of the invention is improved in the retention, compared witha conventional liquid formulation, and further using anupper-pressure-relief airless-type spray container which is differentfrom a conventional container wherein a liquid formulation is pumped upthrough a tube, and it has also become possible to prepare a preparationsuitable for the gel-type formulation. Especially, when using it in anasal spray, it has become possible to carry out a administration bymeans of a nasal spray in an angle of 45° or more in which it had beenimpossible to be sprayed until now.

Furthermore, in an upper-pressure-relief airless-type spray container,the present inventors has improved a body of slidable valve in thecontainer to prepare a spray container characterized in that theresidual rate is low, and the sprayed amount is stable. Thereby it hasbecome possible to prepare a sprayable gel-type skin/mucosa-adhesivepreparation which is safe and economy on the cost.

Therefore, when using the sprayable gel-type skin/mucosa-adhesivepreparation of the invention and the administration system comprisingthe preparation, the absorption and clearance in the treatment ofrhinitis or other disease has been improved, and it is possible to sprayin an angle suitable for the use, furthermore it is possible to almostuse up while keeping a constant amount of one spray shot to the end.Therefore, the present invention has enabled a more effective and usefulpreparation for nasal spray. In addition, the present invention isexpected to become a very useful administration system in the researchand development of drug preparation for intranasal administration whichis a drug administration route for systemic action.

1. A sprayable gel-type skin/mucosa-adhesive preparation comprising agel formulation which contains an active pharmaceutical ingredient in agel base material comprising a skin/mucosa-adhesive agent.
 2. Thesprayable gel-type skin/mucosa-adhesive preparation set forth in claim1, wherein the applied mucosa is a mucosa of nasal cavity, eye, ear,oral cavity, rectum, vagina, or urethra; or the applied skin is a skinof hand, finger, leg, body, groin, scalp, the surround of anus, or thesurround of genitalium.
 3. The sprayable gel-type skin/mucosa-adhesivepreparation set forth in claim 1, wherein the applied mucosa is a mucosaof nasal cavity.
 4. The sprayable gel-type skin/mucosa-adhesivepreparation set forth in claim 1, wherein the skin/mucosa-adhesive agentcomprises carboxy vinyl polymer and/or gellan gum.
 5. The sprayablegel-type skin/mucosa-adhesive preparation set forth in claim 4, whereinthe skin/mucosa-adhesive agent contains 0.1% (w/w) to 2.0% (w/w) carboxyvinyl polymer or gellan gum.
 6. The sprayable gel-typeskin/mucosa-adhesive preparation set forth in claim 4, wherein theskin/mucosa-adhesive agent contains carboxy vinyl polymer and gellan gumin a total amount of 0.2% (w/w) to 4.0% (w/w).
 7. The sprayable gel-typeskin/mucosa-adhesive preparation set forth in claim 1, wherein theskin/mucosa-adhesive agent contains 0.1% (w/w) to 2.0% (w/w) carboxyvinyl polymer, and the viscosity thereof is adjusted by adding anoutside shearing force.
 8. The sprayable gel-type skin/mucosa-adhesivepreparation set forth in claim 7, wherein the skin/mucosa-adhesive agentcontains 0.1% (w/w) to 2.0% (w/w) carboxy vinyl polymer and theviscosity thereof is adjusted to 50 mPa·s to 5000 mPa·s by adding anoutside shearing force.
 9. The sprayable gel-type skin/mucosa-adhesivepreparation set forth in claim 1, wherein the skin/mucosa-adhesive agentcontains 0.1% (w/w) to 2.0% (w/w) carboxy vinyl polymer and theviscosity thereof is adjusted to 50 mPa·s to 5000 mPa·s by adding aviscosity modulating agent and an outside shearing force.
 10. Thesprayable gel-type skin/mucosa-adhesive preparation set forth in claim9, wherein the viscosity modulating agent is selected from a groupconsisting of sodium chloride, potassium chloride and calcium chloride.11. The sprayable gel-type skin/mucosa-adhesive preparation set forth inclaim 4, further comprising a thickening agent for carboxy vinyl polymerwhich is selected from neutral or basic water-soluble amino acids and iscontained in the weight range of 1:0.5 to 1:3 against carboxy vinylpolymer.
 12. The sprayable gel-type skin/mucosa-adhesive preparation setforth in claim 11, wherein the thickening agent is arginine, lysine,and/or ornithine.
 13. The sprayable gel-type skin/mucosa-adhesivepreparation set forth in claim 1, wherein the gel formulation containsan active pharmaceutical ingredient in an amount of 0.001-10% (w/w) inthe gel formulation.
 14. The sprayable gel-type skin/mucosa-adhesivepreparation set forth in claim 1, wherein the active pharmaceuticalingredient is in a dissolved state.
 15. The sprayable gel-typeskin/mucosa-adhesive preparation set forth in claim 1, wherein theactive pharmaceutical ingredient is in a suspended state.
 16. Thesprayable gel-type skin/mucosa-adhesive preparation set forth in claim1, wherein the active pharmaceutical ingredient is in an emulsifiedstate.
 17. An administration system comprising the sprayable gel-typeskin/mucosa-adhesive preparation set forth in claim 1 which is put in aspray container for a gel formulation (upper-pressure-reliefairless-type spray container), which is characterized in that theadministration direction of the spray container can be optionally set inorder to spray the preparation to an affected part for the treatment,i.e., the gel base material can be sprayed at any angle.
 18. Theadministration system set forth in claim 17, wherein the viscosity ofthe gel formulation is in the range between 50 mPa·s and 5000 mPa·s, andthe particle of the formulation sprayed via the spray operation has aviscosity retention rate of 50% or more.
 19. The administration systemset forth in claim 17, wherein the viscosity of the gel formulation isadjusted in the range between 50 mPa·s and 5000 mPa·s by adding anoutside shearing force, and the particle of the formulation sprayed viathe spray operation has a viscosity retention rate of 90% or more. 20.The administration system set forth in claim 17, wherein the meanparticle size of the formulation sprayed is in the range between 10 μmand 100 μm.
 21. The administration system set forth in claim 17, whereinby adding an outside shearing force, the viscosity of the gelformulation is adjusted in the range between 50 mPa·s and 5000 mPa·s,the spray spreading-angle from the spray container is set in the rangebetween 10° and 70°, and the spray spread is set in from uniformitythrough the periphery.
 22. The administration system set forth in claim17, characterized in that the rate of the gel formulation staying in thespray container is not more than 20% when the spray operation has beencompletely impossible through the use, and the rate of the gelformulation sprayed in the range of the prefixed amount ±10% is not lessthan 70%.
 23. The administration system set forth in claim 17,characterized in that the rate of the gel formulation staying in thespray container is not more than 15% when the spray operation has beencompletely impossible through the use, and the rate of the gelformulation sprayed in the range of the prefixed amount ±10% is not lessthan 80%.
 24. The administration system set forth in claim 17, whereinthe spray angle of the spray container for administration can be set inany or all angle between 0° and 360°.